Finasteride Inhibits Human Prostate Cancer Cell Invasion through MMP2 and MMP9 Downregulation

Introduction

The use of the 5-alpha reductase inhibitors (5-ARIs) finasteride and dutasteride for prostate cancer prevention is still under debate. The FDA recently concluded that the increased prevalence of high-grade tumors among 5-ARI-treated patients must not be neglected, and they decided to disallow the use of 5-ARIs for prostate cancer prevention. This study was conducted to verify the effects of finasteride on prostate cell migration and invasion and the related enzymes/proteins in normal human and tumoral prostatic cell lines.

Materials and Methods

RWPE-1, LNCaP, PC3 and DU145 cells were cultivated to 60% confluence and exposed for different periods to either 10 µM or 50 µM finasteride that was diluted in culture medium. The conditioned media were collected and concentrated, and MMP2 and MMP9 activities and TIMP-1 and TIMP-2 protein expression were determined. Cell viability, migration and invasion were analyzed, and the remaining cell extracts were submitted to androgen receptor (AR) detection by western blotting techniques. Experiments were carried out in triplicate.

Results

Cell viability was not significantly affected by finasteride exposure. Finasteride significantly downregulated MMP2 and MMP9 activities in RWPE-1 and PC3 cells and MMP2 in DU145 cells. TIMP-2 expression in RWPE-1 cells was upregulated after exposure. The cell invasion of all four tested cell lines was inhibited by exposure to 50 µM of finasteride, and migration inhibition only occurred for RWPE-1 and LNCaP cells. AR was expressed by LNCaP, RWPE-1 and PC3 cells.

Conclusions

Although the debate on the higher incidence of high-grade prostate cancer among 5-ARI-treated patients remains, our findings indicate that finasteride may attenuate tumor aggressiveness and invasion, which could vary depending on the androgen responsiveness of a patient’s prostate cells.     

Resveratrol Reduces Prostate Cancer Growth and Metastasis by Inhibiting the Akt/MicroRNA-21 Pathway

The consumption of foods containing resveratrol produces significant health benefits. Resveratrol inhibits cancer by reducing cell proliferation and metastasis and by inducing apoptosis. These actions could be explained by its ability to inhibit (ERK-1/2), Akt and suppressing the levels of estrogen and insulin growth factor -1 (IGF-1) receptor. How these processes are manifested into the antitumor actions of resveratrol is not clear. Using microarray studies, we show that resveratrol reduced the expression of various prostate-tumor associated microRNAs (miRs) including miR-21 in androgen-receptor negative and highly aggressive human prostate cancer cells, PC-3M-MM2. This effect of resveratrol was associated with reduced cell viability, migration and invasiveness. Additionally, resveratrol increased the expression of tumor suppressors, PDCD4 and maspin, which are negatively regulated by miR-21. Short interfering (si) RNA against PDCD4 attenuated resveratrol’s effect on prostate cancer cells, and similar effects were observed following over expression of miR-21 with pre-miR-21 oligonucleotides. PC-3M-MM2 cells also exhibited high levels of phospho-Akt (pAkt), which were reduced by both resveratrol and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 (a PI3-kinase inhibitor). MiR-21 expression in these cells appeared to be dependent on Akt, as {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 reduced the levels of miR-21 along with a concurrent increase in PDCD4 expression. These in vitro findings were further corroborated in a severe combined immunodeficient (SCID) mouse xenograft model of prostate cancer. Oral administration of resveratrol not only inhibited the tumor growth but also decreased the incidence and number of metastatic lung lesions. These tumor- and metastatic-suppressive effects of resveratrol were associated with reduced miR-21 and pAkt, and elevated PDCD4 levels. Similar anti-tumor effects of resveratrol were observed in DU145 and LNCaP prostate cancer cells which were associated with suppression of Akt and PDCD4, but independent of miR-21.These data suggest that resveratrol’s anti-tumor actions in prostate cancer could be explained, in part, through inhibition of Akt/miR-21 signaling pathway.     

The inhibitory effects of capillarisin on cell proliferation and invasion of prostate carcinoma cells

Objectives

Capillarisin (Cap), an active component of Artemisia capillaris root extracts, is characterized by its anti‐inflammatory, anti‐oxidant and anti‐cancer properties. Nevertheless, the functions of Cap in prostate cancer have not been fully explored. We evaluated the potential actions of Cap on the cell proliferation, migration and invasion of prostate carcinoma cells.

Materials and methods

Cell proliferation and cell cycle distribution were measured by water‐soluble tetrazolium‐1 and flow cytometry assays. The expression of cyclins, p21, p27, survivin, matrix metallopeptidase (MMP2 and MMP9) were assessed by immunoblotting assays. Effects of Cap on invasion and migration were determined by wound closure and matrigel transmigration assays. The constitutive and interlukin‐6 (IL‐6)‐inducible STAT3 activation of prostate carcinoma cells were determined by immunoblotting and reporter assays.

Results

Capillarisin inhibited androgen‐independent DU145 and androgen‐dependent LNCaP cell growth through the induction of cell cycle arrest at the G0/G1 phase by upregulating p21 and p27 while downregulating expression of cyclin D1, cyclin A and cyclin B. Cap decreased protein expression of survivin, MMP‐2, and MMP‐9 and therefore blocked the migration and invasion of DU145 cells. Cap suppressed constitutive and IL‐6‐inducible STAT3 activation in DU145 and LNCaP cells.

Conclusions

Our data indicate that Cap blocked cell growth by modulation of p21, p27 and cyclins. The inhibitory effects of Cap on survivin, MMP‐2, MMP‐9 and STAT3 activation may account for the suppression of invasion in prostate carcinoma cells. Our data suggest that Cap might be a therapeutic agent in treating advanced prostate cancer with constitutive STAT3 or IL‐6‐inducible STAT3 activation.

     

β-TrCP Inhibition Reduces Prostate Cancer Cell Growth via Upregulation of the Aryl Hydrocarbon Receptor

Background

Prostate cancer is a common and heterogeneous disease, where androgen receptor (AR) signaling plays a pivotal role in development and progression. The initial treatment for advanced prostate cancer is suppression of androgen signaling. Later on, essentially all patients develop an androgen independent stage which does not respond to anti hormonal treatment. Thus, alternative strategies targeting novel molecular mechanisms are required. β-TrCP is an E3 ligase that targets various substrates essential for many aspects of tumorigenesis.

Methodology/Principal Findings

Here we show that β-TrCP depletion suppresses prostate cancer and identify a relevant growth control mechanism. shRNA targeted against β-TrCP reduced prostate cancer cell growth and cooperated with androgen ablation in vitro and in vivo. We found that β-TrCP inhibition leads to upregulation of the aryl hydrocarbon receptor (AhR) mediating the therapeutic effect. This phenomenon could be ligand independent, as the AhR ligand 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) did not alter prostate cancer cell growth. We detected high AhR expression and activation in basal cells and atrophic epithelial cells of human cancer bearing prostates. AhR expression and activation is also significantly higher in tumor cells compared to benign glandular epithelium.

Conclusions/Significance

Together these observations suggest that AhR activation may be a cancer counteracting mechanism in the prostate. We maintain that combining β-TrCP inhibition with androgen ablation could benefit advanced prostate cancer patients.     

Down-regulation of DcR2 sensitizes androgen-dependent prostate cancer LNCaP cells to TRAIL-induced apoptosis

Background

Dysregulation of many apoptotic related genes and androgens are critical in the development, progression, and treatment of prostate cancer. The differential sensitivity of tumour cells to TRAIL-induced apoptosis can be mediated by the modulation of surface TRAIL receptor expression related to androgen concentration. Our previous results led to the hypothesis that downregulation of TRAIL-decoy receptor DcR2 expression following androgen deprivation would leave hormone sensitive normal prostate cells vulnerable to the cell death signal generated by TRAIL via its pro-apoptotic receptors. We tested this hypothesis under pathological conditions by exploring the regulation of TRAIL-induced apoptosis related to their death and decoy receptor expression, as also to hormonal concentrations in androgen-sensitive human prostate cancer, LNCaP, cells.

Results

In contrast to androgen-insensitive PC3 cells, decoy (DcR2) and death (DR5) receptor protein expression was correlated with hormone concentrations and TRAIL-induced apoptosis in LNCaP cells. Silencing of androgen-sensitive DcR2 protein expression by siRNA led to a significant increase in TRAIL-mediated apoptosis related to androgen concentration in LNCaP cells.

Conclusions

The data support the hypothesis that hormone modulation of DcR2 expression regulates TRAIL-induced apoptosis in LNCaP cells, giving insight into cell death induction in apoptosis-resistant hormone-sensitive tumour cells from prostate cancer. TRAIL action and DcR2 expression modulation are potentially of clinical value in advanced tumour treatment.     

Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6

Background

Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung that matches blood perfusion to alveolar ventilation to optimize gas exchange. Recently we have demonstrated that acute but not sustained HPV is critically dependent on the classical transient receptor potential 6 (TRPC6) channel. However, the mechanism of TRPC6 activation during acute HPV remains elusive. We hypothesize that a diacylglycerol (DAG)-dependent activation of TRPC6 regulates acute HPV.

Methods

We investigated the effect of the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) on normoxic vascular tone in isolated perfused and ventilated mouse lungs from TRPC6-deficient and wild-type mice. Moreover, the effects of OAG, the DAG kinase inhibitor {"type":"entrez-nucleotide","attrs":{"text":"R59949","term_id":"830644","term_text":"R59949"}}R59949 and the phospholipase C inhibitor {"type":"entrez-nucleotide","attrs":{"text":"U73122","term_id":"4098075"}}U73122 on the strength of HPV were investigated compared to those on non-hypoxia-induced vasoconstriction elicited by the thromboxane mimeticum U46619.

Results

OAG increased normoxic vascular tone in lungs from wild-type mice, but not in lungs from TRPC6-deficient mice. Under conditions of repetitive hypoxic ventilation, OAG as well as {"type":"entrez-nucleotide","attrs":{"text":"R59949","term_id":"830644","term_text":"R59949"}}R59949 dose-dependently attenuated the strength of acute HPV whereas U46619-induced vasoconstrictions were not reduced. Like OAG, {"type":"entrez-nucleotide","attrs":{"text":"R59949","term_id":"830644","term_text":"R59949"}}R59949 mimicked HPV, since it induced a dose-dependent vasoconstriction during normoxic ventilation. In contrast, {"type":"entrez-nucleotide","attrs":{"text":"U73122","term_id":"4098075"}}U73122, a blocker of DAG synthesis, inhibited acute HPV whereas {"type":"entrez-nucleotide","attrs":{"text":"U73343","term_id":"1688125"}}U73343, the inactive form of {"type":"entrez-nucleotide","attrs":{"text":"U73122","term_id":"4098075"}}U73122, had no effect on HPV.

Conclusion

These findings support the conclusion that the TRPC6-dependency of acute HPV is induced via DAG.     

Postnatal PPARδ Activation and Myostatin Inhibition Exert Distinct yet Complimentary Effects on the Metabolic Profile of Obese Insulin-Resistant Mice

Background

Interventions for T2DM have in part aimed to mimic exercise. Here, we have compared the independent and combined effects of a PPARδ agonist and endurance training mimetic ({"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516) and a myostatin antibody and resistance training mimetic (PF-879) on metabolic and performance outcomes in obese insulin resistant mice.

Methodology/Principal Findings

Male ob/ob mice were treated for 6 weeks with vehicle, {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516, PF-879, or {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516 in combination with PF-879. The effects of the interventions on body composition, glucose homeostasis, glucose tolerance, energy expenditure, exercise capacity and metabolic gene expression were compared at the end of study. {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516 attenuated body weight and fat mass accumulation and increased the expression of genes of oxidative metabolism. In contrast, PF-879 increased body weight by driving muscle growth and altered the expression of genes involved in insulin signaling and glucose metabolism. Despite their differences, both interventions alone improved glucose homeostasis. Moreover, {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516 more effectively improved serum lipids, and PF-879 uniquely increased energy expenditure, exercise capacity and adiponectin levels. When combined the robust effects of {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516 and/or PF-879 on body weight, adiposity, muscle mass, glycemia, serum lipids, energy expenditure and exercise capacity were highly conserved.

Conclusions/Significance

The data, for the first time, demonstrate postnatal inhibition of myostatin not only promotes gains in muscle mass similar to resistance training,but improves metabolic homeostasis. In several instances, these effects were either distinct from or complimentary to those of {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516. The data further suggest that strategies to increase muscle mass, and not necessarily oxidative capacity, may effectively counter insulin resistance and T2DM.     

LncRNAs Expression Signatures of Renal Clear Cell Carcinoma Revealed by Microarray

Background

Long noncoding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. They are aberrantly expressed in many types of cancers. In this study, we described lncRNAs profiles in 6 pairs of human renal clear cell carcinoma (RCCC) and the corresponding adjacent nontumorous tissues (NT) by microarray.

Methodology/Principal Findings

With abundant and varied probes accounting 33,045 LncRNAs in our microarray, the number of lncRNAs that expressed at a certain level could be detected is 17157. From the data we found there were thousands of lncRNAs that differentially expressed (≥2 fold-change) in RCCC tissues compared with NT and 916 lncRNAs differentially expressed in five or more of six RCCC samples. Compared with NT, many lncRNAs were significantly up-regulated or down-regulated in RCCC. Our data showed that down-regulated lncRNAs were more common than up-regulated ones. ENST00000456816, {"type":"entrez-nucleotide","attrs":{"text":"X91348","term_id":"1418768","term_text":"X91348"}}X91348, {"type":"entrez-nucleotide","attrs":{"text":"BC029135","term_id":"23271405","term_text":"BC029135"}}BC029135, {"type":"entrez-nucleotide","attrs":{"text":"NR_024418","term_id":"212286160","term_text":"NR_024418"}}NR_024418 were evaluated by qPCR in sixty-three pairs of RCCC and NT samples. The four lncRNAs were aberrantly expressed in RCCC compared with matched histologically normal renal tissues.

Conclusions/Significance

Our study is the first one to determine genome-wide lncRNAs expression patterns in RCCC by microarray. The results displayed that clusters of lncRNAs were aberrantly expressed in RCCC compared with NT samples, which revealed that lncRNAs differentially expressed in tumor tissues and normal tissues may exert a partial or key role in tumor development. Taken together, this study may provide potential targets for future treatment of RCCC and novel insights into cancer biology.     

Aquaporin3 Is Required for FGF-2-Induced Migration of Human Breast Cancers

Purpose

The aquaporin (AQP) family consists of a number of small integral membrane proteins that transport water and glycerol. AQPs are critical for trans-epithelial fluid transport. Recent reports demonstrated that AQPs, particularly AQP1 and AQP5, are expressed in high grade tumor cells of a variety of tissue origins, and that AQPs are involved in cell migration and metastasis. Based on this background, we examined whether AQP3, another important member of the AQP family, could facilitate cell migration in human breast cancers.

Methods

Potential role of AQP3 was examined using two representative breast cancer cell lines (MDA-MB-231 and Bcap-37). Briefly, AQP3 expression was inhibited with a lentivirus construct that stably expressed shRNA against the AQP3 mRNA. AQP3 expression inhibition was verified with Western blot. Cell migration was examined using a wound scratch assay in the presence of fibroblast growth factor-2 (FGF-2). In additional experiments, AQP3 was inhibited by CuSO₄. Fibroblast growth factor receptor (FGFR) kinase inhibitor PD173074, PI3K inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, and MEK1/2 inhibitor PD98059 were used to dissect the molecular mechanism of FGF-2 induced AQP3 expression.

Results

FGF-2 treatment increased AQP3 expression and induced cell migration in a dose dependent manner. Silencing AQP3 expression by a lentiviral shRNA inhibited FGF-2 induced cell migration. CuSO₄, a water transport inhibitor selective for AQP3, also suppressed FGF-2-induced cell migration. The FGFR kinase inhibitor PD173074, significantly inhibited FGF-2-induced AQP3 expression and cell migration. The PI3K inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 and MEK1/2 inhibitor PD98059 inhibited, but not fully blocked, FGF-2-induced AQP3 expression and cell migration.

Conclusions

AQP3 is required for FGF-2-induced cell migration in cultured human breast cancer cells. Our findings also suggest the importance of FGFR-PI3K and FGFR-ERK signaling in FGF-2-induced AQP3 expression. In summary, our findings suggest a novel function of AQP3 in cell migration and metastasis of breast cancers.     

Receptor-Recognized α2-Macroglobulin Binds to Cell Surface-Associated GRP78 and Activates mTORC1 and mTORC2 Signaling in Prostate Cancer Cells

Objective

Tetrameric α₂-macroglobulin (α₂M), a plasma panproteinase inhibitor, is activated upon interaction with a proteinase, and undergoes a major conformational change exposing a receptor recognition site in each of its subunits. Activated α₂M (α₂M*) binds to cancer cell surface GRP78 and triggers proliferative and antiapoptotic signaling. We have studied the role of α₂M* in the regulation of mTORC1 and TORC2 signaling in the growth of human prostate cancer cells.

Methods

Employing immunoprecipitation techniques and Western blotting as well as kinase assays, activation of the mTORC1 and mTORC2 complexes, as well as down stream targets were studied. RNAi was also employed to silence expression of Raptor, Rictor, or GRP78 in parallel studies.

Results

Stimulation of cells with α₂M* promotes phosphorylation of mTOR, TSC2, S6-Kinase, 4EBP, Akt^T308, and Akt^S473 in a concentration and time-dependent manner. Rheb, Raptor, and Rictor also increased. α₂M* treatment of cells elevated mTORC1 kinase activity as determined by kinase assays of mTOR or Raptor immunoprecipitates. mTORC1 activity was sensitive to {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 and rapamycin or transfection of cells with GRP78 dsRNA. Down regulation of Raptor expression by RNAi significantly reduced α₂M*-induced S6-Kinase phosphorylation at T389 and kinase activity in Raptor immunoprecipitates. α₂M*-treated cells demonstrate about a twofold increase in mTORC2 kinase activity as determined by kinase assay of Akt^S473 phosphorylation and levels of p-Akt^S473 in mTOR and Rictor immunoprecipitates. mTORC2 activity was sensitive to {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 and transfection of cells with GRP78 dsRNA, but insensitive to rapamycin. Down regulation of Rictor expression by RNAi significantly reduces α₂M*-induced phosphorylation of Akt^S473 phosphorylation in Rictor immunoprecipitates.

Conclusion

Binding of α₂M* to prostate cancer cell surface GRP78 upregulates mTORC1 and mTORC2 activation and promotes protein synthesis in the prostate cancer cells.     

Long Noncoding RNAs Expression Patterns Associated with Chemo Response to Cisplatin Based Chemotherapy in Lung Squamous Cell Carcinoma Patients

Background

There is large variability among lung squamous cell carcinoma patients in response to treatment with cisplatin based chemotherapy. LncRNA is potentially a new type of predictive marker that can identify subgroups of patients who benefit from chemotherapy and it will have great value for treatment guidance.

Methods

Differentially expressed lncRNAs and mRNA were identified using microarray profiling of tumors with partial response (PR) vs. with progressive disease (PD) from advanced lung squamous cell carcinoma patients treated with cisplatin based chemotherapy and validated by quantitative real-time PCR (qPCR). Furthermore, the expression of {"type":"entrez-nucleotide","attrs":{"text":"AC006050","term_id":"117414223","term_text":"AC006050"}}AC006050.3-003 was assessed in another 60 tumor samples.

Results

Compared with the PD samples, 953 lncRNAs were consistently upregulated and 749 lncRNAs were downregulated consistently among the differentially expressed lncRNAs in PR samples (Fold Change≥2.0-fold, p <0.05). Pathway analyses showed that some classical pathways, including “Nucleotide excision repair,” that participated in cisplatin chemo response were differentially expressed between PR and PD samples. Coding-non-coding gene co-expression network identified many lncRNAs, such as lncRNA {"type":"entrez-nucleotide","attrs":{"text":"AC006050","term_id":"117414223","term_text":"AC006050"}}AC006050.3-003, that potentially played a key role in chemo response. The expression of lncRNA {"type":"entrez-nucleotide","attrs":{"text":"AC006050","term_id":"117414223","term_text":"AC006050"}}AC006050.3-003 was significantly lower in PR samples compared to the PD samples in another 60 lung squamous cell carcinoma patients. Receiver operating characteristic curve analysis revealed that lncRNA {"type":"entrez-nucleotide","attrs":{"text":"AC006050","term_id":"117414223","term_text":"AC006050"}}AC006050.3-003 was a valuable biomarker for differentiating PR patients from PD patients with an area under the curve of 0.887 (95% confidence interval 0.779, 0.954).

Conclusions

LncRNAs seem to be involved in cisplatin-based chemo response and may serve as biomarkers for treatment response and candidates for therapy targets in lung squamous cell carcinoma.     

Small molecule sensitization to TRAIL is mediated via nuclear localization,phosphorylation and inhibition of chaperone activity of Hsp27

The small chaperone protein Hsp27 confers resistance to apoptosis, and therefore is an attractive anticancer drug target. We report here a novel mechanism underlying the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitizing activity of the small molecule {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511, an inactive analog of the phosphoinositide 3-kinase inhibitor inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, in HeLa cells that are refractory to TRAIL-induced apoptosis. On the basis of the fact that {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511 is derived from {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, itself derived from quercetin, and earlier findings indicating that quercetin and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 affected Hsp27 expression, we investigated whether {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511 sensitized cancer cells to TRAIL via a conserved inhibitory effect on Hsp27. We provide evidence that upon treatment with {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511, Hsp27 is progressively sequestered in the nucleus, thus reducing its protective effect in the cytosol during the apoptotic process. {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511-induced nuclear translocation of Hsp27 is linked to its sustained phosphorylation via activation of p38 kinase and MAPKAP kinase 2 and the inhibition of PP2A. Furthermore, Hsp27 phosphorylation leads to the subsequent dissociation of its large oligomers and a decrease in its chaperone activity, thereby further compromising the death inhibitory activity of Hsp27. Furthermore, genetic manipulation of Hsp27 expression significantly affected the TRAIL sensitizing activity of {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511, which corroborated the Hsp27 targeting activity of {"type":"entrez-nucleotide","attrs":{"text":"LY303511","term_id":"1257646067","term_text":"LY303511"}}LY303511. Taken together, these data indicate a novel mechanism of small molecule sensitization to TRAIL through targeting of Hsp27 functions, rather than its overall expression, leading to decreased cellular protection, which could have therapeutic implications for overcoming chemotherapy resistance in tumor cells.     

Virtual Screening as a Strategy for the Identification of Xenobiotics Disrupting Corticosteroid Action

Background

Impaired corticosteroid action caused by genetic and environmental influence, including exposure to hazardous xenobiotics, contributes to the development and progression of metabolic diseases, cardiovascular complications and immune disorders. Novel strategies are thus needed for identifying xenobiotics that interfere with corticosteroid homeostasis. 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) and mineralocorticoid receptors (MR) are major regulators of corticosteroid action. 11β-HSD2 converts the active glucocorticoid cortisol to the inactive cortisone and protects MR from activation by glucocorticoids. 11β-HSD2 has also an essential role in the placenta to protect the fetus from high maternal cortisol concentrations.

Methods and Principal Findings

We employed a previously constructed 3D-structural library of chemicals with proven and suspected endocrine disrupting effects for virtual screening using a chemical feature-based 11β-HSD pharmacophore. We tested several in silico predicted chemicals in a 11β-HSD2 bioassay. The identified antibiotic lasalocid and the silane-coupling agent {"type":"entrez-nucleotide","attrs":{"text":"AB110873","term_id":"44885399","term_text":"AB110873"}}AB110873 were found to concentration-dependently inhibit 11β-HSD2. Moreover, the silane {"type":"entrez-nucleotide","attrs":{"text":"AB110873","term_id":"44885399","term_text":"AB110873"}}AB110873 was shown to activate MR and stimulate mitochondrial ROS generation and the production of the proinflammatory cytokine interleukin-6 (IL-6). Finally, we constructed a MR pharmacophore, which successfully identified the silane {"type":"entrez-nucleotide","attrs":{"text":"AB110873","term_id":"44885399","term_text":"AB110873"}}AB110873.

Conclusions

Screening of virtual chemical structure libraries can facilitate the identification of xenobiotics inhibiting 11β-HSD2 and/or activating MR. Lasalocid and {"type":"entrez-nucleotide","attrs":{"text":"AB110873","term_id":"44885399","term_text":"AB110873"}}AB110873 belong to new classes of 11β-HSD2 inhibitors. The silane {"type":"entrez-nucleotide","attrs":{"text":"AB110873","term_id":"44885399","term_text":"AB110873"}}AB110873 represents to the best of our knowledge the first industrial chemical shown to activate MR. Furthermore, the MR pharmacophore can now be used for future screening purposes.     

Genome sequences published outside of Standards in Genomic Sciences, March-April 2012

The purpose of this table is to provide the community with a citable record of publications of ongoing genome sequencing projects that have led to a publication in the scientific literature. While our goal is to make the list complete, there is no guarantee that we may have omitted one or more publications appearing in this time frame. Readers and authors who wish to have publications added to subsequent versions of this list are invited to provide the bibliographic data for such references to the SIGS editorial office.

Phylum Euryarchaeota

• Halococcus hamelinensis, sequence accession PRJNA80845 [1]
• “Methanocella conradii” HZ254, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP003243","term_id":"379319823","term_text":"CP003243"}}CP003243 [2]
• Thermococcus litoralis NS-C, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHVB00000000","term_id":"374743520","term_text":"AHVB00000000"}}AHVB00000000 [3]

Phylum Crenarchaeota

• Candidatus Nitrosopumilus salaria” BD31, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AEXL00000000","term_id":"386807666","term_text":"AEXL00000000"}}AEXL00000000 [4]
• Candidatus Nitrosoarchaeum limnia, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHJG00000000","term_id":"367466343","term_text":"AHJG00000000"}}AHJG00000000 [5]

Phylum Deinococcus-Thermus

• Deinococcus gobiensis, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP002536","term_id":"324314064","term_text":"CP002536"}}CP002536 [6]

Phylum Proteobacteria

• Aggregatibacter actinomycetemcomitans strain ANH9381, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP003099","term_id":"365745154","term_text":"CP003099"}}CP003099 [7]
• Alishewanella jeotgali, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHTH00000000","term_id":"374571619","term_text":"AHTH00000000"}}AHTH00000000 [8]
• Enterobacter aerogenes KCTC 2190, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP002824","term_id":"334732565","term_text":"CP002824"}}CP002824 [9]
• Escherichia coli O104:H4, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AFOB02000092","term_id":"340739517","term_text":"AFOB02000092"}}AFOB02000092 [10]
• Helicobacter pylori strains 17874, sequence accession PRJNA76569 [11]
• Helicobacter pylori strains P79, sequence accession PRJNA76567 [11]
• Janthinobacterium sp. Strain PAMC 25724, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHHB00000000","term_id":"372292151","term_text":"AHHB00000000"}}AHHB00000000 [12]
• Klebsiella oxytoca KCTC 1686, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP003218","term_id":"365906294","term_text":"CP003218"}}CP003218 [13]
• Klebsiella pneumoniae subsp. pneumoniae HS11286, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP003200","term_id":"364515570","term_text":"CP003200"}}CP003200 (chromosome), {"type":"entrez-nucleotide","attrs":{"text":"CP003223","term_id":"365803686","term_text":"CP003223"}}CP003223 (plasmid pKPHS1), {"type":"entrez-nucleotide","attrs":{"text":"CP003224","term_id":"365803828","term_text":"CP003224"}}CP003224 (plasmid pKPHS2), {"type":"entrez-nucleotide","attrs":{"text":"CP003225","term_id":"365803989","term_text":"CP003225"}}CP003225 (plasmid pKPHS3), {"type":"entrez-nucleotide","attrs":{"text":"CP003226","term_id":"365804142","term_text":"CP003226"}}CP003226 (plasmid pKPHS4), {"type":"entrez-nucleotide","attrs":{"text":"CP003227","term_id":"365804147","term_text":"CP003227"}}CP003227 (plasmid pKPHS5), {"type":"entrez-nucleotide","attrs":{"text":"CP003228","term_id":"365804153","term_text":"CP003228"}}CP003228 (plasmid pKPHS6) [14]
• Oceanimonas sp. GK1, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP003171","term_id":"372983507","term_text":"CP003171"}}CP003171 [15]
• “Pseudogulbenkiania ferrooxidans” Strain 2002, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"NZ_ACIS01000000","term_id":"224827334","term_text":"ref||NZ_ACIS01000000"}}NZ_ACIS01000000 [16]
• Pseudomonas extremaustralis 14-3b, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHIP00000000","term_id":"371721769","term_text":"AHIP00000000"}}AHIP00000000 [17]
• Pseudomonas sp. Strain PAMC 25886, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHHC00000000","term_id":"372002201","term_text":"AHHC00000000"}}AHHC00000000 [18]
• Psychrobacter, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHVZ00000000","term_id":"375126956","term_text":"AHVZ00000000"}}AHVZ00000000 [19]
• Rahnella sp. Strain Y9602, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP002505","term_id":"321165934","term_text":"CP002505"}}CP002505 [20]
• Rhizobium sp. Strain PDO1-076, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHZC00000000","term_id":"375058045","term_text":"AHZC00000000"}}AHZC00000000 [21]
• Rhodospirillum photometricum DSM122, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"HE663493","term_id":"378401447","term_text":"HE663493"}}HE663493 [22]
• “Rickettsia sibirica sibirica”, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHIZ00000000","term_id":"374669031","term_text":"AHIZ00000000"}}AHIZ00000000 [23]
• Rickettsia sibirica subsp. mongolitimonae strain HA-91, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHZB00000000","term_id":"375318263","term_text":"AHZB00000000"}}AHZB00000000 [24]
• Salmonella enterica subsp. enterica Serotype Enteritidis Strain LA5, sequence accession [25]
• Salmonella enterica subsp. enterica Serotype Senftenberg Strain SS209, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CAGQ00000000","term_id":"379987603","term_text":"CAGQ00000000"}}CAGQ00000000 [26]
• Salmonella enterica subsp. enterica Serovar Typhi P-stx-12, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP003278","term_id":"374352002","term_text":"CP003278"}}CP003278 (chromosome) and {"type":"entrez-nucleotide","attrs":{"text":"CP003279","term_id":"374356693","term_text":"CP003279"}}CP003279 (plasmid) [27]
• Sphingomonas echinoides ATCC 14820, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHIR00000000","term_id":"366040205","term_text":"AHIR00000000"}}AHIR00000000 [28]
• Strain HIMB55, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AGIF00000000","term_id":"374304583","term_text":"AGIF00000000"}}AGIF00000000 [29]
• Vibrio harveyi CAIM 1792, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHHQ00000000","term_id":"374671508","term_text":"AHHQ00000000"}}AHHQ00000000 [30]
• Wolbachia Strain wAlbB, sequence accession {"type":"entrez-nucleotide-range","attrs":{"text":"CAGB01000001 to CAGB01000165","start_term":"CAGB01000001","end_term":"CAGB01000165","start_term_id":"371933004","end_term_id":"371931774"}}CAGB01000001 to CAGB01000165 [31]
• Xanthomonas axonopodis pv. punicae Strain LMG 859, sequence accession {"type":"entrez-nucleotide-range","attrs":{"text":"CAGJ01000001 to CAGJ01000217","start_term":"CAGJ01000001","end_term":"CAGJ01000217","start_term_id":"372556075","end_term_id":"372551622"}}CAGJ01000001 to CAGJ01000217 [32]

Phylum Tenericutes

• Mycoplasma hyorhinis Strain GDL-1, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP003231","term_id":"367460291","term_text":"CP003231"}}CP003231 [33]

Phylum Firmicutes

• Bacillus subtilis, sequence accession BGSCID 3A27 through BGSCID 28A4 [34]
• Clostridium difficile Strain CD37, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHJJ00000000","term_id":"371930118","term_text":"AHJJ00000000"}}AHJJ00000000 [35]
• Clostridium perfringens, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AFES00000000","term_id":"380306484","term_text":"AFES00000000"}}AFES00000000 [36]
• Lactobacillus fructivorans KCTC 3543, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AEQY00000000","term_id":"316986063","term_text":"AEQY00000000"}}AEQY00000000 [37]
• Lactococcus lactis IO-1, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AP012281","term_id":"374672113","term_text":"AP012281"}}AP012281 [38]
• Lactobacillus plantarum strain NC8, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AGRI00000000","term_id":"376011245","term_text":"AGRI00000000"}}AGRI00000000 [39]
• Paenibacillus dendritiformis C454, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHKH00000000","term_id":"374393106","term_text":"AHKH00000000"}}AHKH00000000 [40]
• Paenibacillus sp. Strain Aloe-11, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AGFI00000000","term_id":"374477730","term_text":"AGFI00000000"}}AGFI00000000 [41]
• “Peptoniphilus rhinitidis” 1-13^T, sequence accession {"type":"entrez-nucleotide-range","attrs":{"text":"BAEW01000001 to BAEW01000056","start_term":"BAEW01000001","end_term":"BAEW01000056","start_term_id":"374722129","end_term_id":"374722074"}}BAEW01000001 to BAEW01000056 [42]
• Streptococcus macedonicus ACA-DC 198, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"HE613569","term_id":"372283141","term_text":"HE613569"}}HE613569 and {"type":"entrez-nucleotide","attrs":{"text":"HE613570","term_id":"372285142","term_text":"HE613570"}}HE613570 [43]
• Staphylococcus aureus VC40, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP003033","term_id":"374362062","term_text":"CP003033"}}CP003033 [44]
• Streptococcus infantarius subsp. infantarius Strain CJ18, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP003295","term_id":"374681091","term_text":"CP003295"}}CP003295 (chromosome), {"type":"entrez-nucleotide","attrs":{"text":"CP003296","term_id":"374682963","term_text":"CP003296"}}CP003296 (plasmid) [45]
• Streptococcus macedonicus ACA-DC 198, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"HE613569","term_id":"372283141","term_text":"HE613569"}}HE613569 (chromosome), {"type":"entrez-nucleotide","attrs":{"text":"HE613570","term_id":"372285142","term_text":"HE613570"}}HE613570 (plasmid pSMA198) [46]

Phylum Actinobacteria

• Actinoplanes sp. SE50/110, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"CP003170","term_id":"359832573","term_text":"CP003170"}}CP003170 [47]
• Amycolatopsis sp. Strain ATCC 39116, sequence accession [48]
• Nocardia cyriacigeorgica GUH-2, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"FO082843","term_id":"374843763","term_text":"FO082843"}}FO082843 [49]
• Salinibacterium sp., sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHWA00000000","term_id":"375323651","term_text":"AHWA00000000"}}AHWA00000000 [50]
• Streptomyces acidiscabies 84-104, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AHBF00000000","term_id":"372137622","term_text":"AHBF00000000"}}AHBF00000000 [51]

Non-Bacterial genomes

• Bluetongue Virus Serotype 2, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AJ783905","term_id":"70907482","term_text":"AJ783905"}}AJ783905 (Seg-6) and {"type":"entrez-nucleotide","attrs":{"text":"JQ681257","term_id":"383932043","term_text":"JQ681257"}}JQ681257 (Seg-1), {"type":"entrez-nucleotide","attrs":{"text":"JQ681257","term_id":"383932043","term_text":"JQ681257"}}JQ681257 (Seg-1), {"type":"entrez-nucleotide","attrs":{"text":"JQ681258","term_id":"383932045","term_text":"JQ681258"}}JQ681258 (Seg-2), {"type":"entrez-nucleotide","attrs":{"text":"JQ681259","term_id":"383932047","term_text":"JQ681259"}}JQ681259 (Seg-3), {"type":"entrez-nucleotide","attrs":{"text":"JQ681260","term_id":"383932049","term_text":"JQ681260"}}JQ681260 (Seg-4), {"type":"entrez-nucleotide","attrs":{"text":"JQ681261","term_id":"383932051","term_text":"JQ681261"}}JQ681261 (Seg-5), {"type":"entrez-nucleotide","attrs":{"text":"JQ681262","term_id":"383932053","term_text":"JQ681262"}}JQ681262 (Seg-7), JQ6812563 (Seg-8), JQ6812564 (Seg-9), to {"type":"entrez-nucleotide","attrs":{"text":"JQ681265","term_id":"383932059","term_text":"JQ681265"}}JQ681265 (Seg-10) [52]
• Virus Serotype 1, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"AJ585111","term_id":"118420282","term_text":"AJ585111"}}AJ585111 (Seg-2), {"type":"entrez-nucleotide","attrs":{"text":"AJ586659","term_id":"47826214","term_text":"AJ586659"}}AJ586659 (Seg-6), {"type":"entrez-nucleotide","attrs":{"text":"JQ282770","term_id":"383215071","term_text":"JQ282770"}}JQ282770 (Seg-1), {"type":"entrez-nucleotide","attrs":{"text":"JQ282771","term_id":"383215073","term_text":"JQ282771"}}JQ282771 (Seg-3), {"type":"entrez-nucleotide","attrs":{"text":"JQ282772","term_id":"383215075","term_text":"JQ282772"}}JQ282772 (Seg-4), {"type":"entrez-nucleotide","attrs":{"text":"JQ282773","term_id":"383215077","term_text":"JQ282773"}}JQ282773 (Seg-5), {"type":"entrez-nucleotide","attrs":{"text":"JQ282774","term_id":"383215079","term_text":"JQ282774"}}JQ282774 (Seg-7), {"type":"entrez-nucleotide","attrs":{"text":"JQ282775","term_id":"383215081","term_text":"JQ282775"}}JQ282775 (Seg-8), {"type":"entrez-nucleotide","attrs":{"text":"JQ282776","term_id":"383215083","term_text":"JQ282776"}}JQ282776 (Seg-9), and {"type":"entrez-nucleotide","attrs":{"text":"JQ282777","term_id":"383215085","term_text":"JQ282777"}}JQ282777 (Seg-10) [52]
• Chloroplast genome of Erycina pusilla, sequence accession JF_746994 [53]
• Danio rerio, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"JQ434101","term_id":"384872525","term_text":"JQ434101"}}JQ434101 [54]
• Enterococcal Bacteriophage SAP6, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"JF731128","term_id":"343411857","term_text":"JF731128"}}JF731128 [55]
• Eubenangee virus, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"JQ070376","term_id":"383513837","term_text":"JQ070376"}}JQ070376 through {"type":"entrez-nucleotide","attrs":{"text":"JQ070385","term_id":"383513855","term_text":"JQ070385"}}JQ070385 [56]
• Fujian/411-like viruses, sequence accession {"type":"entrez-nucleotide-range","attrs":{"text":"CY087969 to CY088568","start_term":"CY087969","end_term":"CY088568","start_term_id":"380506411","end_term_id":"380507803"}}CY087969 to CY088568 [57]
• Hantavirus Variant of Rio Mamoré Virus, Maripa Virus, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"JQ611712","term_id":"384382977","term_text":"JQ611712"}}JQ611712 (segment S), {"type":"entrez-nucleotide","attrs":{"text":"JQ611713","term_id":"384382979","term_text":"JQ611713"}}JQ611713 (segment M), and {"type":"entrez-nucleotide","attrs":{"text":"JQ611714","term_id":"384382981","term_text":"JQ611714"}}JQ611714 (segment L) [58]
• Pata virus, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"JQ070386","term_id":"383513857","term_text":"JQ070386"}}JQ070386 through {"type":"entrez-nucleotide","attrs":{"text":"JQ070395","term_id":"383513875","term_text":"JQ070395"}}JQ070395 [59]
• Porcine Circovirus 2, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"JQ413808","term_id":"383215164","term_text":"JQ413808"}}JQ413808 [60]
• Porcine Reproductive and Respiratory Syndrome Virus, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"JQ326271","term_id":"382929416","term_text":"JQ326271"}}JQ326271 [61]
• Streptococcus mutans Phage M102AD, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"DQ386162","term_id":"88698119","term_text":"DQ386162"}}DQ386162 [62]
• Tilligery virus, sequence accession {"type":"entrez-nucleotide","attrs":{"text":"JQ070366","term_id":"383513817","term_text":"JQ070366"}}JQ070366 through {"type":"entrez-nucleotide","attrs":{"text":"JQ070375","term_id":"383513835","term_text":"JQ070375"}}JQ070375 [63]

     

Hypoxic Conditioned Medium from Rat Cerebral Cortical Cells Enhances the Proliferation and Differentiation of Neural Stem Cells Mainly through PI3-K/Akt Pathways

Purpose

To investigate the effects of hypoxic conditioned media from rat cerebral cortical cells on the proliferation and differentiation of neural stem cells (NSCs) in vitro, and to study the roles of PI3-K/Akt and JNK signal transduction pathways in these processes.

Methods

Cerebral cortical cells from neonatal Sprague–Dawley rat were cultured under hypoxic and normoxic conditions; the supernatant was collected and named ‘hypoxic conditioned medium’ (HCM) and ‘normoxic conditioned medium’ (NCM), respectively. We detected the protein levels (by ELISA) of VEGF and BDNF in the conditioned media and mRNA levels (by RT-PCR) in cerebral cortical cells. The proliferation (number and size of neurospheres) and differentiation (proportion of neurons and astrocytes over total cells) of NSCs was assessed. {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 and SP600125, inhibitors of PI3-K/Akt and JNK, respectively, were applied, and the phosphorylation levels of PI3-K, Akt and JNK were measured by western blot.

Results

The protein levels and mRNA expressions of VEGF and BDNF in 4% HCM and 1% HCM were both higher than that of those in NCM. The efficiency and speed of NSCs proliferation was enhanced in 4% HCM compared with 1% HCM. The highest percentage of neurons and lowest percentage of astrocytes was found in 4% HCM. However, the enhancement of NSCs proliferation and differentiation into neurons accelerated by 4% HCM was inhibited by {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 and SP600125, with {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 having a stronger inhibitory effect. The increased phosphorylation levels of PI3-K, Akt and JNK in 4% HCM were blocked by {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 and SP600125.

Conclusions

4%HCM could promote NSCs proliferation and differentiation into high percentage of neurons, these processes may be mainly through PI3-K/Akt pathways.     

Shikonin selectively induces apoptosis in human prostate cancer cells through the endoplasmic reticulum stress and mitochondrial apoptotic pathway

Background

Despite the recent progress in screening and therapy, a majority of prostate cancer cases eventually attain hormone refractory and chemo-resistant attributes. Conventional chemotherapeutic strategies are effective at very high doses for only palliative management of these prostate cancers. Therefore chemo-sensitization of prostate cancer cells could be a promising strategy for increasing efficacy of the conventional chemotherapeutic agents in prostate cancer patients. Recent studies have indicated that the chemo-preventive natural agents restore the pro-apoptotic protein expression and induce endoplasmic reticulum stress (ER stress) leading to the inhibition of cellular proliferation and activation of the mitochondrial apoptosis in prostate cancer cells. Therefore reprogramming ER stress-mitochondrial dependent apoptosis could be a potential approach for management of hormone refractory chemoresistant prostate cancers. We aimed to study the effects of the natural naphthoquinone Shikonin in human prostate cancer cells.

Results

The results indicated that Shikonin induces apoptosis in prostate cancer cells through the dual induction of the endoplasmic reticulum stress and mitochondrial dysfunction. Shikonin induced ROS generation and activated ER stress and calpain activity. Moreover, addition of antioxidants attenuated these effects. Shikonin also induced the mitochondrial apoptotic pathway mediated through the enhanced expression of the pro-apoptotic Bax and inhibition of Bcl-2, disruption of the mitochondrial membrane potential (MMP) followed by the activation of caspase-9, caspase-3, and PARP cleavage.

Conclusion

The results suggest that shikonin could be useful in the therapeutic management of hormone refractory prostate cancers due to its modulation of the pro-apoptotic ER stress and mitochondrial apoptotic pathways.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-015-0127-1) contains supplementary material, which is available to authorized users.