共查询到20条相似文献,搜索用时 15 毫秒
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Hongliang Yu Li Yin Xuesong Jiang Xiujin Sun Jing Wu Hao Tian Xianshu Gao Xia He 《PloS one》2014,9(12)
Background
Laboratory studies have shown the anti-tumor effect of metformin on prostate cancer. However, recent epidemiological studies have yielded inconclusive results.Methods
We searched PubMed database from the inception to May 30 2014 for studies which assessed the effect of metformin use on cancer risk of prostate cancer, biochemical recurrence (BCR) and all-cause mortality of patients with prostate cancer. The pooled results and 95% confidence intervals (CIs) were estimated by random-effect model.Results
Twenty-one studies were eligible according to the inclusion criteria. Based on the pooled results of available observational studies, metformin use was significantly associated with a decreased cancer risk (14 datasets, 963991 male subjects, odds ratio: 0.91, 95% CI: 0.85–0.97) and BCR (6 datasets, 2953 patients, hazard ratio: 0.81, 95% CI: 0.68–0.98) of prostate cancer. However, the association of metformin use with all-cause mortality of patients with prostate cancer was not significant (5 datasets, 9241 patients, hazard ratio: 0.86, 95% CI: 0.64–1.14).Conclusion
Results suggest that metformin use appears to be associated with a significant reduction in the cancer risk and BCR of prostate cancer, but not in all-cause mortality of patients with prostate cancer. 相似文献3.
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4.
Beshay N.M. Zordoky Diana BarkCarrie L. Soltys Miranda M. SungJason R.B. Dyck 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Metformin has been shown to have a strong anti-proliferative effect in many breast cancer cell lines, mainly due to the activation of the energy sensing kinase, AMP-activated protein kinase (AMPK). MDA-MB-231 cells are aggressive and invasive breast cancer cells that are known to be resistant to several anti-cancer agents as well as to the anti-proliferative effect of metformin. As metformin is a glucose lowering drug, we hypothesized that normoglycemia will sensitize MDA-MB-231 cells to the anti-proliferative effect of metformin.Methods
MDA-MB-231 cells were treated with increasing metformin concentrations in hyperglycemic or normoglycemic conditions. The growth inhibitory effect of metformin was assessed by MTT assay. The expression of several proteins involved in cell proliferation was measured by Western blotting.Results
In agreement with previous studies, treatment with metformin did not inhibit the growth of MDA-MB-231 cells cultured in hyperglycemic conditions. However, metformin significantly inhibited MDA-MB-231 growth when the cells were cultured in normoglycemic conditions. In addition, we show that metformin-treatment of MDA-MB-231 cells cultured in normoglycemic conditions and not in hyperglycemic conditions caused a striking activation of AMPK, and an AMPK-dependent inhibition of multiple molecular signaling pathways known to control protein synthesis and cell proliferation.Conclusion
Our data show that normoglycemia sensitizes the triple negative MDA-MB-231 breast cancer cells to the anti-proliferative effect of metformin through an AMPK-dependent mechanism.General significance
These findings suggest that tight normoglycemic control may enhance the anti-proliferative effect of metformin in diabetic cancer patients. 相似文献5.
Alessandra Silvestri Francesco Palumbo Ignazio Rasi Daniela Posca Theodora Pavlidou Serena Paoluzi Luisa Castagnoli Giovanni Cesareni 《PloS one》2015,10(8)
Introduction
Metformin is proposed as adjuvant therapy in cancer treatment because of its ability to limit cancer incidence by negatively modulating the PI3K/AKT/mTOR pathway. In vitro, in addition to inhibiting cancer cell proliferation, metformin can also induce apoptosis. The molecular mechanism underlying this second effect is still poorly characterized and published data are often contrasting. We investigated how nutrient availability can modulate metformin-induced apoptosis in three breast cancer cell lines.Material and Methods
MCF7, SKBR3 and MDA-MB-231 cells were plated in MEM medium supplemented with increasing glucose concentrations or in DMEM medium and treated with 10 mM metformin. Cell viability was monitored by Trypan Blue assay and treatment effects on Akt/mTOR pathway and on apoptosis were analysed by Western Blot. Moreover, we determined the level of expression of pyruvate kinase M2 (PKM2), a well-known glycolytic enzyme expressed in cancer cells.Results
Our results showed that metformin can induce apoptosis in breast cancer cells when cultured at physiological glucose concentrations and that the pro-apoptotic effect was completely abolished when cells were grown in high glucose/high amino acid medium. Induction of apoptosis was found to be dependent on AMPK activation but, at least partially, independent of TORC1 inactivation. Finally, we showed that, in nutrient-poor conditions, metformin was able to modulate the intracellular glycolytic equilibrium by downregulating PKM2 expression and that this mechanism was mediated by AMPK activation.Conclusion
We demonstrated that metformin induces breast cancer cell apoptosis and PKM2 downregulation only in nutrient-poor conditions. Not only glucose levels but also amino acid concentration can influence the observed metformin inhibitory effect on the mTOR pathway as well as its pro-apoptotic effect. These data demonstrate that the reduction of nutrient supply in tumors can increase metformin efficacy and that modulation of PKM2 expression/activity could be a promising strategy to boost metformin anti-cancer effect. 相似文献6.
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Audrey Dayon Leyre Brizuela Claire Martin Catherine Mazerolles Nelly Pirot Nicolas Doumerc Leonor Nogueira Muriel Golzio Justin Teissié Guy Serre Pascal Rischmann Bernard Malavaud Olivier Cuvillier 《PloS one》2009,4(11)
Background
Sphingosine kinase-1 (SphK1) is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival.Methodology/Principal Findings
Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT) to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway—by negatively impacting SphK1 activity—could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity.Conclusions/Significance
We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a compensatory mechanism allowing prostate cancer cells to survive in androgen-depleted environment, giving support to its inhibition as a potential therapeutic strategy to delay/prevent the transition to androgen-independent prostate cancer. 相似文献8.
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Abdellatif Essabbani Luis Garcia Maria Josè Zonetti Tommaso Fisco Sabina Pucci Gilles Chiocchia 《PloS one》2013,8(2)
Background
In prostate cancer the secreted form of clusterin (sCLU) has been described as an anti-apoptotic protein whose expression is increased after therapeutic intervention, whereas, the nuclear protein form nCLU was reported to have pro-apoptotic properties.Methodology
In order to provide new therapeutic approaches targeting CLU, we developed a strategy based on exon skipping by using a lentiviral construct to preferentially induce the nuclear spliced form of the protein. The molecular construct was transduced in LNCaP cells for testing the modulation of sensitivity of the transduced cells to pro-apoptotic stress.Results and Conclusions
We showed an increase of nCLU/sCLU expression ratio in the prostate cancer cell line “LNCaP” after lentiviral vector-U7 nCLU transduction. Moreover, we showed a significant inhibition of cell proliferation in nCLU-U7 LNCaP cells after treatment with cisplatin and after exposure to ionizing radiation compared to control cells. Finally, we showed that nCLU-U7 LNCaP cells exposure to UV-C significantly reduced an increase of cell death compared to control. Finally, we showed that modulating nCLU expression had profound impact on Ku70/Bax interaction as well as Rad17 expression which could be a key mechanism in sensitizing cells to cell death. In conclusion, this is the first report showing that increasing of nCLU/sCLU expression ratio by using an “on demand alternative splicing” strategy successfully increased sensitivity to radiotherapy and chemotherapy of prostate cancer cells. 相似文献11.
Hui Li Lu-Yan Shen Wan-Pu Yan Bin Dong Xiao-Zheng Kang Liang Dai Yong-Bo Yang Hao Fu He-Li Yang Hai-Tao Zhou Chuan Huang Zhen Liang Hong-Chao Xiong Ke-Neng Chen 《PloS one》2015,10(6)
Background
We observed abnormal HOXB7 expression in esophageal squamous cell carcinoma (ESCC) previously. This study was to evaluate the prognostic significance of HOXB7 and reveal the potential mechanism.Methods
Immunohistochemistry was used to confirm the abnormal expression of HOXB7 in ESCC. The prognostic significance of HOXB7 expression was analyzed in two independent cohorts. RNAi was used to establish two stable HOXB7-knockdown cell strains. CCK8 assay, cell growth curve assay, colony formation assay, flow cycle analysis and tumorigenicity assay in nude mice were employed to investigate the effect of HOXB7 on proliferation in vitro and in vivo.Results
Immunohistochemistry confirmed the abnormal expression of HOXB7 in ESCC compared with paracancerous mucosa (18/23 vs. 9/23, p=0.039). HOXB7 expression was positively correlated with the T stage, lymph node metastasis and TNM stage. The median survival of patients with high HOXB7 expression was significantly shorter than that with low expression (45 months vs. 137 months, p = 0.007 for cohort 1; 19 months vs. 34 months, p = 0.001 for cohort 2). Multivariate survival analysis showed that HOXB7 expression was another independent prognostic factor (HR [95% CI] = 0.573 [0.341–0.963], p = 0.036 for cohort 1; HR [95%CI] = 0.543 [0.350–0.844], p = 0.024 for cohort 2). Experiments in vitro and in vivo showed that after knockdown of HOXB7, the proliferation rate dropped, growth rate descended, colony-formation ability reduced, G1-phase arrest occurred and the tumorigenicity reduced remarkably.Conclusions
HOXB7 could promote cancer cell proliferation and might be an independent prognostic factor for patients with ESCC. 相似文献12.
Cesaltina Lorenzoni Alba Vilajeliu Carla Carrilho Mamudo R. Ismail Paola Castillo Orvalho Augusto Alberto L. García-Basteiro Mohsin Sidat Silvia de Sanjosé Clara Menéndez Jaume Ordi 《PloS one》2015,10(6)
Background
Very limited information is available regarding the incidence of cancer in sub-Saharan Africa. We analyzed changes in cancer patterns from 1991 to 2008 in Maputo (Mozambique).Methods
We calculated the rates of incidence of different cancer sites by sex in the 5-year age-group of the population of Maputo city as well as age-standardized rates (ASRs) and average annual percentage changes (AAPC).Results
Over the 18-year study period a total of 12,674 cases of cancer (56.9% females) were registered with an overall increase in the risk of cancer in both sexes. In males, the most common cancers were those of the prostate, Kaposi sarcoma (KS) and the liver. Prostate cancer showed the most dramatic increase over the whole study period (AAPC +11.3%; 95% CI: 9.7–13.0), with an ASR of 61.7 per 105 in 2003–2008. In females, the most frequent cancers were of the uterine cervix, the breast and KS, with the former increasing along the whole study period (AAPC + 4.7%; 95% CI: 3.4–6) with an ASR of 62.0 per 105 in 2003–2008 as well as breast cancer (AAPC +6.5%; 95%CI: 4.3–8.7).Conclusions
Overall, the risk of cancer rose in both sexes during the study period, particularly among cancers associated with westernization of lifestyles (prostate, breast), combined with increasingly rising incidences or limited changes in cancers associated with infection and poverty (uterine cervix, liver). Moreover, the burden of AIDS-associated cancers has shown a marked increase. 相似文献13.
Yeona Cho Jee Suk Chang Koon Ho Rha Sung Joon Hong Young Deuk Choi Won Sik Ham Jun Won Kim Jaeho Cho 《PloS one》2016,11(1)
Purpose/Objectives
Treatment of the primary tumor reportedly improves survival in several types of metastatic cancer. We herein evaluated the efficacy and toxicity of radiotherapy for the primary tumor in prostate cancer with metastasis.Materials/Methods
The study cohort included 140 men with metastatic prostate cancer at initial diagnosis. Metastatic sites were divided into 4 groups as follows: solitary bone, 2–4 bones, ≥5 bones, and visceral organs. Patient, tumor, and treatment characteristics, and clinical outcomes were compared between patients treated with (prostate radiotherapy [PRT] group) or without radiotherapy to the primary tumor.Results
Patients in PRT group presented with a statistically significantly younger age (p = .02), whereas other characteristics showed no significant difference. Overall survival (OS) and biochemical failure-free survival (BCFFS) were improved in PRT patients (3-year OS: 69% vs. 43%, p = 0.004; 3-year BCFFS: 52% vs. 16%, p = 0.002). Multivariate analysis identified PRT as a significant predictor of both OS (hazard ratio [HR] = 0.43, p = 0.015). None of the 38 PRT patients experienced severe (grade ≥3) genitourinary or gastrointestinal toxicity.Conclusions
Our data suggest that radiotherapy to the primary tumor was associated with improved OS and BCFFS in metastatic prostate cancer. The results of this study warrant prospective controlled clinical trials of this approach in stage IV prostate cancer patients with limited extent of bone metastasis and good performance status. 相似文献14.
Gregory KJ Zhao B Bielenberg DR Dridi S Wu J Jiang W Huang B Pirie-Shepherd S Fannon M 《PloS one》2010,5(10):e13428
Background
Vitamin D binding protein-macrophage activating factor (DBP-maf) is a potent inhibitor of tumor growth. Its activity, however, has been attributed to indirect mechanisms such as boosting the immune response by activating macrophages and inhibiting the blood vessel growth necessary for the growth of tumors.Methods and Findings
In this study we show for the first time that DBP-maf exhibits a direct and potent effect on prostate tumor cells in the absence of macrophages. DBP-maf demonstrated inhibitory activity in proliferation studies of both LNCaP and PC3 prostate cancer cell lines as well as metastatic clones of these cells. Flow cytometry studies with annexin V and propidium iodide showed that this inhibitory activity is not due to apoptosis or cell death. DBP-maf also had the ability to inhibit migration of prostate cancer cells in vitro. Finally, DBP-maf was shown to cause a reduction in urokinase plasminogen activator receptor (uPAR) expression in prostate tumor cells. There is evidence that activation of this receptor correlates with tumor metastasis.Conclusions
These studies show strong inhibitory activity of DBP-maf on prostate tumor cells independent of its macrophage activation. 相似文献15.
Monica Franciosi Giuseppe Lucisano Emanuela Lapice Giovanni F. M. Strippoli Fabio Pellegrini Antonio Nicolucci 《PloS one》2013,8(8)
Aims/Hypothesis
Diabetes treatments were related with either an increased or reduced risk of cancer. There is ongoing debate about a potential protective action of metformin. To summarize evidence on the association between metformin and risk of cancer and cancer mortality in patients with diabetes.Methods
Data source: MEDLINE and EMBASE (January 1966-April 2012). We selected randomized studies comparing metformin and other hypoglycaemic agents and observational studies exploring the association between exposure to metformin and cancer. Outcomes were cancer mortality, all malignancies and site-specific cancers.Results
Of 25307 citations identified, 12 randomized controlled trials (21,595 patients) and 41 observational studies (1,029,389 patients) met the inclusion criteria. In observational studies there was a significant association of exposure to metformin with the risk of cancer death [6 studies, 24,410 patients, OR:0.65, 95%CI: 0.53-0.80], all malignancies [18 studies, 561,836 patients, OR:0.73, 95%CI: 0.61-0.88], liver [8 studies, 312,742 patients, OR:0.34; 95%CI: 0.19-0.60] colorectal [12 studies, 871,365 patients, OR:0.83, 95%CI: 0.74–0.92], pancreas [9 studies, 847,248 patients, OR:0.56, 95%CI: 0.36–0.86], stomach [2 studies, 100701 patients, OR:0.83, 95%CI: 0.76–0.91], and esophagus cancer [2 studies, 100694 patients, OR:0.90, 95%CI: 0.83–0.98]. No significant difference of risk was observed in randomized trials. Metformin was not associated with the risk of: breast cancer, lung cancer, ovarian cancer, uterus cancer, prostate cancer, bladder cancer, kidney cancer, and melanoma.Conclusions/Interpretation
Results suggest that Metformin might be associated with a significant reduction in the risk of cancer and cancer-related mortality. Randomized trials specifically designed to evaluate the efficacy of metformin as an anticancer agent are warranted. 相似文献16.
Haakon E. Meyer Nathalie C. St?er Sven O. Samuelsen Rune Blomhoff Trude E. Robsahm Magritt Brustad Edward L. Giovannucci Tone Bj?rge 《PloS one》2016,11(3)
Objective
A number of observational studies have shown an inverse association between circulating 25-hydroxyvitamin D and total mortality, but a reverse J-shaped association has also been reported. In a large nested case-control study, serum-25-hydroxyvitamin D (s-25(OH)D) was positively associated with incident prostate cancer. Based on the same study population, the primary aim of the present study was to investigate the association between s-25(OH)D and total mortality.Methods
Men participating in population based health screenings during 1981–1991 and enrolled in a nested case-control study were followed throughout 2007 with respect to all-cause and cause-specific mortality. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards regression.Results
In men with prostate cancer (n = 2282), there was a significant inverse association between s-25(OH)D and total mortality after controlling for potential confounders (HR = 1.25 (95% CI 1.05–1.50), s-25(OH)D <50 nmol/l versus s-25(OH)D ≥50 nmol/l). The corresponding figure among controls (n = 2147) was HR = 1.15 (95% CI 0.88–1.50) and in the total study population HR = 1.19 (95% CI 1.03–1.38). For cause-specific deaths, we found no significant associations.Conclusions
In this study population, s-25(OH)D was inversely associated with total mortality during more than two decades of follow-up, despite, as previous reported, high s-25(OH)D was associated with increased risk of prostate cancer. 相似文献17.
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Background
Small cell lung cancer (SCLC) is a recalcitrant malignancy with distinct biologic properties. Antibody targeting therapy has been actively investigated as a new drug modality.Methods
We tested the expression of IGF-1R and calculated the survival in 61 SCLC patients. We also evaluated the anti-tumor effects of anti-IGF-1R monoclonal antibody Figitumumab (CP) on SCLC, and tried two drug combinations to improve CP therapy.Results
Our clinical data suggested that high IGF-1R expression was correlated with low SCLC patient survival. We then demonstrated the effect of CP was likely through IGF-1R blockage and down-regulation without IGF-1R auto-phosphorylation and PI3K/AKT activation. However, we observed elevated MEK/ERK activation upon CP treatment in SCLC cells, and this MEK/ERK activation was enhanced by ß-arrestin1 knockdown while attenuated by ß-arrestin2 knockdown. We found both MEK/ERK inhibitor and metformin could enhance CP treatment in SCLC cells. We further illustrated the additive effect of metformin was likely through promoting further IGF-1R down-regulation.Conclusion
Our results highlighted the potential of anti-IGF-1R therapy and the adjuvant therapy strategy with either MEK/ERK inhibitor or metformin to target SCLC, warranting further studies. 相似文献19.
Objective
In human prostate cancer cells, a selective Epac agonist, 8-CPT-2Me-cAMP, upregulates cell proliferation and survival via activation of Ras-MAPK and PI- 3-kinase-Akt-mTOR signaling cascades. Here we examine the role of inflammatory mediators in Epac1-induced cellular proliferation by determining the expression of the pro-inflammatory markers p-cPLA2, COX-2, and PGE2 in prostate cancer cells treated with 8-CPT-2Me-cAMP.Methods
We employed inhibitors of COX-2, mTORC1, and mTORC2 to probe cyclic AMP-dependent pathways in human prostate cancer cells. RNAi targeting Epac1, Raptor, and Rictor was also employed in these studies.Results
8-CPT-2Me-cAMP treatment caused a 2–2.5-fold increase of p-cPLA2S505, COX-2, and PGE2 levels in human prostate cancer cell lines. Pretreatment of cells with the COX-2 inhibitor SC-58125 or the EP4 antagonist AH-23848, or with an inhibitor of mTORC1 and mTORC2, Torin1, significantly reduced the Epac1-dependent increase of p-cPLA2 and COX-2, p-S6-kinaseT389, and p-AKTS473. In addition, Epac1-induced protein and DNA synthesis were greatly reduced upon pretreatment of cells with either COX-2, EP4, or mTOR inhibitors. Transfection of prostate cancer cells with Epac1 dsRNA, Raptor dsRNA, or Rictor dsRNA profoundly reduced Epac1-dependent increases in p-cPLA2 and COX-2.Conclusion
We show that Epac1, a downstream effector of cAMP, functions as a pro-inflammatory modulator in prostate cancer cells and promotes cell proliferation and survival by upregulating Ras-MAPK, and PI 3-kinase-Akt-mTOR signaling. 相似文献20.
Adaikkalam Vellaichamy Zoltán Dezs? Lellean JeBailey Arul M. Chinnaiyan Arun Sreekumar Alexey I. Nesvizhskii Gilbert S. Omenn Andrej Bugrim 《PloS one》2010,5(6)