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1.
Veeramani S Chou YW Lin FC Muniyan S Lin FF Kumar S Xie Y Lele SM Tu Y Lin MF 《Free radical biology & medicine》2012,53(1):95-108
Steroid hormones exhibit diverse biological activities. Despite intensive studies on steroid function at the genomic level, their nongenomic actions remain an enigma. In this study, we investigated the role of reactive oxygen species (ROS) in androgen-stimulated prostate cancer (PCa) cell proliferation. In androgen-treated PCa cells, increased cell growth and ROS production correlated with elevated p66Shc protein, an authentic oxidase. This growth stimulation was blocked by antioxidants. Further, elevated expression of p66Shc protein by cDNA transfection encoding wild-type protein, but not a redox-deficient (W134F) mutant, was associated with increased PCa cell proliferation. Conversely, knockdown of p66Shc expression by shRNA resulted in diminished cell growth. Increased p66Shc expression in PCa cells enhanced their tumorigenicity in xenograft animals. Importantly, p66Shc protein level is higher in clinical prostate adenocarcinomas than in adjacent noncancerous cells. Expression of redox-deficient p66Shc mutant protein abolished androgen-stimulated cell growth. In androgen-treated, H(2)O(2)-treated, and p66Shc cDNA-transfected PCa cells, cellular prostatic acid phosphatase, an authentic tyrosine phosphatase, was inactivated by reversible oxidation; subsequently, ErbB-2 was activated by phosphorylation at tyrosine-1221/1222. These results together support the notion that androgens induce ROS production through the elevation of p66Shc protein, which inactivates tyrosine phosphatase activity for the activation of interacting tyrosine kinase, leading to increased cell proliferation and enhanced tumorigenicity. Our results thus suggest that p66Shc protein functions at the critical junction point between androgens and tyrosine phosphorylation signaling in human PCa cells. 相似文献
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Iris Alchanati Carmit Teicher Galit Cohen Vivian Shemesh Haim M. Barr Philippe Nakache Danny Ben-Avraham Anna Idelevich Itzchak Angel Nurit Livnah Shmuel Tuvia Yuval Reiss Daniel Taglicht Omri Erez 《PloS one》2009,4(12)
Background
The topoisomerases Top1, Top2α and Top2β are important molecular targets for antitumor drugs, which specifically poison Top1 or Top2 isomers. While it was previously demonstrated that poisoned Top1 and Top2β are subject to proteasomal degradation, this phenomena was not demonstrated for Top2α.Methodology/Principal Findings
We show here that Top2α is subject to drug induced proteasomal degradation as well, although at a lower rate than Top2β. Using an siRNA screen we identified Bmi1 and Ring1A as subunits of an E3 ubiquitin ligase involved in this process. We show that silencing of Bmi1 inhibits drug-induced Top2α degradation, increases the persistence of Top2α-DNA cleavage complex, and increases Top2 drug efficacy. The Bmi1/Ring1A ligase ubiquitinates Top2α in-vitro and cellular overexpression of Bmi1 increases drug induced Top2α ubiquitination. A small-molecular weight compound, identified in a screen for inhibitors of Bmi1/Ring1A ubiquitination activity, also prevents Top2α ubiquitination and drug-induced Top2α degradation. This ubiquitination inhibitor increases the efficacy of topoisomerase 2 poisons in a synergistic manner.Conclusions/Significance
The discovery that poisoned Top2α is undergoing proteasomal degradation combined with the involvement of Bmi1/Ring1A, allowed us to identify a small molecule that inhibits the degradation process. The Bmi1/Ring1A inhibitor sensitizes cells to Top2 drugs, suggesting that this type of drug combination will have a beneficial therapeutic outcome. As Bmi1 is also a known oncogene, elevated in numerous types of cancer, the identified Bmi1/Ring1A ubiquitin ligase inhibitors can also be potentially used to directly target the oncogenic properties of Bmi1. 相似文献3.
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Metastatic castration-resistant (CR) prostate cancer (PCa) is a lethal disease for which no effective treatment is currently available. p66Shc is an oxidase previously shown to promote androgen-independent cell growth through generation of reactive oxygen species (ROS) and is elevated in clinical PCa and multiple CR PCa cell lines. We hypothesize p66Shc also increases the migratory activity of PCa cells through ROS and investigate the associated mechanism. Using the transwell assay, our study reveals that the level of p66Shc protein correlates with cell migratory ability across several PCa cell lines. Furthermore, we show hydrogen peroxide treatment induces migration of PCa cells that express low levels of p66Shc in a dose-dependent manner, while antioxidants inhibit migration. Conversely, PCa cells that express high levels of endogenous p66Shc or by cDNA transfection possess increased cell migration which is mitigated upon p66Shc shRNA transfection or expression of oxidase-deficient dominant-negative p66Shc W134F mutant. Protein microarray and immunoblot analyses reveal multiple proteins, including ErbB-2, AKT, mTOR, ERK, FOXM1, PYK2 and Rac1, are activated in p66Shc-elevated cells. Their involvement in PCa migration was examined using respective small-molecule inhibitors. The role of Rac1 was further validated using cDNA transfection and, significantly, p66Shc is found to promote lamellipodia formation through Rac1 activation. In summary, the results of our current studies clearly indicate p66Shc also regulates PCa cell migration through ROS-mediated activation of migration-associated proteins, notably Rac1. 相似文献
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Background
Programmed cell death 4 (PDCD4), originally identified as the neoplastic transformation inhibitor, was attenuated in various cancer types. Our previous study demonstrated a continuous down-regulation of PDCD4 expression in the sequence of normal-borderline-malignant ovarian tissue samples and a significant correlation of PDCD4 expression with disease-free survival. The objective of the current study was to further investigate the function and modulation of PDCD4 in ovarian cancer cells.Principal Findings
We demonstrated that ectopic PDCD4 expression significantly inhibited cell proliferation by inducing cell cycle arrest at G1 stage and up-regulation of cell cycle inhibitors of p27 and p21. Cell migration and invasion were also inhibited by PDCD4. PDCD4 over-expressing cells exhibited elevated phosphatase and tensin homolog (PTEN) and inhibited protein kinase B (p-Akt). In addition, the expression of PDCD4 was up-regulated and it was exported to the cytoplasm upon serum withdrawal treatment, but it was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K) inhibitor prevented the degradation of PDCD4, indicating the involvement of PI3K-Akt pathway in the modulation of PDCD4.Conclusion
PDCD4 may play a critical function in arresting cell cycle progression at key checkpoint, thus inhibiting cell proliferation, as well as suppressing tumour metastasis. The PI3K-Akt pathway was implied to be involved in the regulation of PDCD4 degradation in ovarian cancer cells. In response to the stress condition, endogenous PDCD4 was able to shuttle between cell compartments to perform its diverted functions. 相似文献7.
Background
Early prostate cancer antigen (EPCA) has been shown a prostate cancer (PCa)-associated nuclear matrix protein, however, its serum status and prognostic power in PCa are unknown. The goals of this study are to measure serum EPCA levels in a cohort of patients with PCa prior to the treatment, and to evaluate the clinical value of serum EPCA.Methods
Pretreatment serum EPCA levels were determined with an ELISA in 77 patients with clinically localized PCa who underwent radical prostatectomy and 51 patients with locally advanced or metastatic disease who received primary androgen deprivation therapy, and were correlated with clinicopathological variables and disease progression. Serum EPCA levels were also examined in 40 healthy controls.Results
Pretreatment mean serum EPCA levels were significantly higher in PCa patients than in controls (16.84±7.60 ng/ml vs. 4.12±2.05 ng/ml, P<0.001). Patients with locally advanced and metastatic PCa had significantly higher serum EPCA level than those with clinically localized PCa (22.93±5.28 ng/ml and 29.41±8.47 ng/ml vs. 15.17±6.03 ng/ml, P = 0.014 and P<0.001, respectively). Significantly elevated EPCA level was also found in metastatic PCa compared with locally advanced disease (P<0.001). Increased serum EPCA levels were significantly and positively correlated with Gleason score and clinical stage, but not with PSA levels and age. On multivariate analysis, pretreatment serum EPCA level held the most significantly predictive value for the biochemical recurrence and androgen-independent progression among pretreatment variables (HR = 4.860, P<0.001 and HR = 5.418, P<0.001, respectively).Conclusions
Serum EPCA level is markedly elevated in PCa. Pretreatment serum EPCA level correlates significantly with the poor prognosis, showing prediction potential for PCa progression. 相似文献8.
Jing Liu Shaobo Yang Zhiqiang Wang Xiao Chen Ziqi Zhang 《Journal of biomedical science》2013,20(1):74
Background
Intestinal polyps may further develop into colon cancer; the pathogenesis is not clear. The p53 gene is an important anti-cancer gene in the body, which is suppressed in cancer. The ubiquitin E3 ligase A20 (A20) plays a role in regulating the activities of epithelial cells. This study was designed to investigate the role of the colon polyp epithelium-derived A20 in the pathogenesis of colon cancer.Results
Eighty-eight colon cancer patients and 136 colon polyp patients were recruited into this study. Human colon cancer tissue, the epithelium of adenomas polyp and hyperplastic polyp showed high levels of A20, which had a positive correlation with the cancerous tendency of colon polyps. The levels of A20 were much higher in the adenomas and hyperplastic polyps than that in the inflammatory polyps; the latter showed less cancerous tendency. A20 bound p53 to form complexes in colon cancer tissue and colon polyps. Over expression of A20 suppresses P53 protein levels in the HEK293 cells.Conclusions
A20 may play an important role in the cancerous tendency of colon polyposis. 相似文献9.
Background
Prostate cancer recurrence involves increased growth of cancer epithelial cells, as androgen dependent prostate cancer progresses to castrate resistant prostate cancer (CRPC) following initial therapy. Understanding CRPC prostate regrowth will provide opportunities for new cancer therapies to treat advanced disease.Methodology/Principal Findings
Elevated chemokine expression in the prostate stroma of a castrate resistant mouse model, Tgfbr2fspKO, prompted us to look at the involvement of bone marrow derived cells (BMDCs) in prostate regrowth. We identified bone marrow cells recruited to the prostate in GFP-chimeric mice. A dramatic increase in BMDC recruitment for prostate regrowth occurred three days after exogenous testosterone implantation. Recruitment led to incorporation of BMDCs within the prostate epithelia. Immunofluorescence staining suggested BMDCs in the prostate coexpressed androgen receptor; p63, a basal epithelial marker; and cytokeratin 8, a luminal epithelial marker. A subset of the BMDC population, mesenchymal stem cells (MSCs), were specifically found to be incorporated in the prostate at its greatest time of remodeling. Rosa26 expressing MSCs injected into GFP mice supported MSC fusion with resident prostate epithelial cells through co-localization of β-galactosidase and GFP during regrowth. In a human C4-2B xenograft model of CRPC, MSCs were specifically recruited. Injection of GFP-labeled MSCs supported C4-2B tumor progression by potentiating canonical Wnt signaling. The use of MSCs as a targeted delivery vector for the exogenously expressed Wnt antagonist, secreted frizzled related protein-2 (SFRP2), reduced tumor growth, increased apoptosis and potentiated tumor necrosis.Conclusions/Significance
Mesenchymal stem cells fuse with prostate epithelia during the process of prostate regrowth. MSCs recruited to the regrowing prostate can be used as a vehicle for transporting genetic information with potential therapeutic effects on castrate resistant prostate cancer, for instance by antagonizing Wnt signaling through SFRP2. 相似文献10.
Jingying Zhang Xin Yao Rongbin Yu Jianling Bai Yun Sun Mao Huang Ian M Adcock Peter J Barnes 《Respiratory research》2010,11(1):50
Background
The non-invasive assessment of airway inflammation is potentially advantageous in asthma management. Exhaled carbon monoxide (eCO) measurement is cheap and has been proposed to reflect airway inflammation and oxidative stress but current data are conflicting. The purpose of this meta-analysis is to determine whether eCO is elevated in asthmatics, is regulated by steroid treatment and reflects disease severity and control.Methods
A systematic search for English language articles published between 1997 and 2009 was performed using Medline, Embase and Cochrane databases. Observational studies comparing eCO in non-smoking asthmatics and healthy subjects or asthmatics before and after steroid treatment were included. Data were independently extracted by two investigators and analyzed to generate weighted mean differences using either a fixed or random effects meta-analysis depending upon the degree of heterogeneity.Results
18 studies were included in the meta-analysis. The eCO level was significantly higher in asthmatics as compared to healthy subjects and in intermittent asthma as compared to persistent asthma. However, eCO could not distinguish between steroid-treated asthmatics and steroid-free patients nor separate controlled and partly-controlled asthma from uncontrolled asthma in cross-sectional studies. In contrast, eCO was significantly reduced following a course of corticosteroid treatment.Conclusions
eCO is elevated in asthmatics but levels only partially reflect disease severity and control. eCO might be a potentially useful non-invasive biomarker of airway inflammation and oxidative stress in nonsmoking asthmatics. 相似文献11.
Syed Khaja AS Helczynski L Edsjö A Ehrnström R Lindgren A Ulmert D Andersson T Bjartell A 《PloS one》2011,6(10):e26539
Background
Wnt5a is a non-canonical secreted glycoprotein of the Wnt family that plays an important role in cancer development and progression. Previous studies report that Wnt5a is upregulated in prostate cancer and suggested that Wnt5a affects migration and invasion of prostate tumor cell. This study aimed to evaluate the prognostic value of Wnt5a protein expression in prostate cancer tissue and its potential to predict outcome after radical prostatectomy in patients with localized prostate cancer.Methodology and Results
Immunohistochemical analysis of a tissue microarray containing prostate specimens of 503 patients with localized prostate cancer showed significantly higher Wnt5a protein expression in cancer compared to benign cores from the same patients (p<0.0001). Patients with high expression of Wnt5a protein had significantly better outcome in terms of time to biochemical recurrence compared to patients with low expression levels (p = 0.001, 95%CI 1.361–3.570, Hazard''s ratio 2.204). A combination of high Wnt5a expression with low levels of Ki-67 or androgen receptor expression had even better outcome compared to all other groups. Furthermore, we found that Wnt5a expression significantly correlated with VEGF and with Ki-67 and androgen receptor expression, although not highly significant. In vitro, we demonstrated that recombinant Wnt5a decreased invasion of 22Rv1 and DU145 cells and that siRNA knockdown of endogenous Wnt5a protein led to increased invasion of 22Rv1 and LNCaP cells.Conclusion
We demonstrate that preserved overexpression of Wnt5a protein in patients with localized prostate cancer predicts a favorable outcome after surgery. This finding together with our in vitro data demonstrating the ability of Wnt5a to impair the invasive properties of prostate cancer cells, suggests a tumor suppressing effect of Wnt5a in localized prostate cancer. These results indicate that Wnt5a can be used as a predictive marker and that it also is a plausible therapeutic target for treatment of localized prostate cancer. 相似文献12.
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Background
Currently available methods for diagnosis and staging of prostate cancer lack the sensitivity to distinguish between patients with indolent prostate cancer and those requiring radical treatment. Alterations in key adherens (AJ) and tight junction (TJ) components have been hailed as potential biomarkers for prostate cancer progression but the majority of research has been carried out on individual molecules.Objective
To elucidate a panel of biomarkers that may help distinguish dormant prostate cancer from aggressive metastatic disease.Methods
We analysed the expression of 7 well known AJ and TJ components in cell lines derived from normal prostate epithelial tissue (PNT2), non-invasive (CAHPV-10) and invasive prostate cancer (LNCaP, DU145, PC-3) using gene expression, western blotting and immunofluorescence techniques.Results
Claudin 7, α –catenin and β-catenin protein expression were not significantly different between CAHPV-10 cells and PNT2 cells. However, in PC-3 cells, protein levels for claudin 7, α –catenin were significantly down regulated (−1.5 fold, p = <.001) or undetectable respectively. Immunofluoresence showed β-catenin localisation in PC-3 cells to be cytoplasmic as opposed to membraneous.Conclusion
These results suggest aberrant Claudin 7, α – and β-catenin expression and/or localisation patterns may be putative markers for distinguishing localised prostate cancer from aggressive metastatic disease when used collectively. 相似文献16.
Richard Manns Andre Schmandke Antonio Schmandke Prem Jareonsettasin Geoffrey Cook Martin E. Schwab Christine Holt Roger Keynes 《PloS one》2014,9(1)
Background
The protein Nogo-A regulates axon growth in the developing and mature nervous system, and this is carried out by two distinct domains in the protein, Nogo-A-Δ20 and Nogo-66. The differences in the signalling pathways engaged in axon growth cones by these domains are not well characterized, and have been investigated in this study.Methodology/Principal Findings
We analyzed growth cone collapse induced by the Nogo-A domains Nogo-A-Δ20 and Nogo-66 using explanted chick dorsal root ganglion neurons growing on laminin/poly-lysine substratum. Collapse induced by purified Nogo-A-Δ20 peptide is dependent on protein synthesis whereas that induced by Nogo-66 peptide is not. Nogo-A-Δ20-induced collapse is accompanied by a protein synthesis-dependent rise in RhoA expression in the growth cone, but is unaffected by proteasomal catalytic site inhibition. Conversely Nogo-66-induced collapse is inhibited ∼50% by proteasomal catalytic site inhibition.Conclusion/Significance
Growth cone collapse induced by the Nogo-A domains Nogo-A-Δ20 and Nogo-66 is mediated by signalling pathways with distinguishable characteristics concerning their dependence on protein synthesis and proteasomal function. 相似文献17.
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Introduction
XMRV is a gammaretrovirus that was thought to be associated with prostate cancer (PC) and chronic fatigue syndrome (CFS) in humans until recently. The virus is culturable in various cells of human origin like the lymphocytes, NK cells, neuronal cells, and prostate cell lines. MicroRNAs (miRNA), which regulate gene expression, were so far not identified in cells infected with XMRV in culture.Methods
Two prostate cell lines (LNCaP and DU145) and two primary cells, Peripheral Blood Lymphocytes [PBL] and Monocyte-derived Macrophages [MDM] were infected with XMRV. Total mRNA was extracted from mock- and virus-infected cells at 6, 24 and 48 hours post infection and evaluated for microRNA profile in a microarray.Results
MicroRNA expression profiles of XMRV-infected continuous prostate cancer cell lines differ from that of virus-infected primary cells (PBL and MDMs). miR-193a-3p and miRPlus-E1245 observed to be specific to XMRV infection in all 4 cell types. While miR-193a-3p levels were down regulated miRPlus-E1245 on the other hand exhibited varied expression profile between the 4 cell types.Discussion
The present study clearly demonstrates that cellular microRNAs are expressed during XMRV infection of human cells and this is the first report demonstrating the regulation of miR193a-3p and miRPlus-E1245 during XMRV infection in four different human cell types. 相似文献19.
Background
Malignant gliomas represent one group of tumors that poorly respond to ionizing radiation (IR) alone or combined with chemotherapeutic agents because of the intrinsic or acquired resistance. In this study, TIP-1 was identified as one novel protein that confers resistance of glioma cells to IR.Methodology/Principal Findings
Meta-analysis indicated that high TIP-1 expression levels correlate with the poor prognosis of human malignant gliomas after radiotherapy. Studies with established human glioma cell lines demonstrated that TIP-1 depletion with specific shRNAs sensitized the cells to IR, whereas an ectopic expression of TIP-1 protected the glioma cells from the IR-induced DNA damage and cell death. Biochemical studies indicated that TIP-1 protein promoted p53 ubiquitination and resulted in a reduced p53 protein level. Furthermore, p53 and its ubiquitination are required for the TIP-1 regulated cellular response to IR. A yeast two-hybrid screening identified that TIP-1, through its single PDZ domain, binds to the carboxyl terminus of LZAP that has been studied as one tumor suppressor functioning through ARF binding and p53 activation. It was revealed that the presence of TIP-1 enhances the protein association between LZAP and ARF and modulates the functionality of ARF/HDM2 toward multi-ubiquitination of p53, while depleting TIP-1 rescued p53 from polyubiquitination and degradation in the irradiated glioma cells. Studies with a mouse xenograft model indicated that depleting TIP-1 within D54 cells improved the tumor growth control with IR.Conclusions/Significance
This study provided the first evidence showing that TIP-1 modulates p53 protein stability and is involved in the radioresistance of malignant gliomas, suggesting that antagonizing TIP-1 might be one novel approach to sensitize malignant gliomas to radiotherapy. 相似文献20.
Maria Katsogiannou Charbel El Boustany Florian Gackiere Philippe Delcourt Anne Athias Pascal Mariot Etienne Dewailly Nathalie Jouy Christophe Lamaze Gabriel Bidaux Brigitte Mauroy Natalia Prevarskaya Christian Slomianny 《PloS one》2009,4(9)