Metformin represses androgen‐dependent and androgen‐independent prostate cancers by targeting androgen receptor

Wang, Yan; Liu, Gaolei; Tong, Dali; Parmar, Henna; Hasenmayer, Donald; Yuan, Wenqiang; Zhang, Dianzheng; Jiang, Jun

doi:10.1002/pros.23000

Cited by 57 publications

(72 citation statements)

References 23 publications

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“…21 Previous studies demonstrated that metformin restrained prostate cancer cell proliferation, migration, and invasion and enhanced apoptosis. 13,22 These findings are consistent with our results. In contrast, Miyoshi et al suggested that metformin inhibited the growth of hepatoma cells by inducing G1 cell cycle arrest.…”

Section: Discussionsupporting

confidence: 93%

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Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

Chen

et al. 2016

Cancer Biology & Therapy

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Metformin has been reported to inhibit the growth of various types of cancers, including prostate cancer. Yet the mode of anti-cancer action of metformin and the underlying mechanisms remain not fully elucidated. We hypothesized that the antitumorigenic effects of metformin are mediated through upregulation of pigment epithelium-derived factor (PEDF) expression in prostate cancer cells. In this report, metformin treatment significantly inhibited the proliferation and colony formation of prostate cancer cells, in a dose-and time-dependent manner. Meanwhile, Metformin markedly suppressed migration and invasion and induced apoptosis of both LNCaP and PC3 cancer cells. Metformin also reduced PC3 tumor growth in BALB/c nude mice in vivo. Furthermore, metformin treatment was associated with higher PEDF expression in both prostate cancer cells and tumor tissue. Taken together, metformin inhibits prostate cancer cell proliferation, migration, invasion and tumor growth, and these activities are mediated by upregulation of PEDF expression. These findings provide a novel insight into the molecular functions of metformin as an anticancer agent.Abbreviations: PEDF, pigment epithelium-derived factor; AMPK, 5 0 -AMP-activated protein kinase; mTOR, mammalian target of rapamycin; IL8, interleukin8; MAPK, mitogen-activated protein kinase; Met, metformin; qPCR, quantitative polymerase chain reaction; PBS, fetal bovine serum; CCK8, Cell Counter Kit-8; PBS, phosphate-buffered saline solution; PtdIns, propidium iodide; SD, standard deviation

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Section: Discussionsupporting

confidence: 93%

“…Besides its main molecular target, AMPK, metformin also directly inhibits the mTOR pathway, 11 lipogenesis, 12 and the androgen receptor signaling pathway. 13 Nevertheless, the molecular mechanisms underlying these beneficial effects in prostate cancer remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

Chen

et al. 2016

Cancer Biology & Therapy

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“…Metformin, a potential anticancer agent, has been shown to inhibit growth and induce apoptosis though AMPK-dependent and -independent signaling pathways in CRPC cells5556. One study found that combination of metformin with other therapeutic agents, such as anti-AR agent bicalutamide, enhanced the growth inhibition of CRPC via AR-mediated signaling57. While metformin has been shown to inhibit NF-κB signaling in several other studies5859, the regulation of metformin to MUC1 signaling remains elusive60.…”

Section: Discussionmentioning

confidence: 99%

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

Xiang

Zhang

Tang

et al. 2016

Sci Rep

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Prostate cancer is the second most common cause of cancer-related deaths worldwide. The mucin 1 (MUC1) oncoprotein is highly expressed in human prostate cancers with aggressive features. However, the role for MUC1 in occurrence and progression of castration-resistant prostate cancer (CRPC) remained elusive. In this study, we showed that solamargine, a major steroidal alkaloid glycoside, inhibited the growth of CRPC cells, which was enhanced in the presence of metformin. Furthermore, we found that solamargine increased phosphorylation of AMPKα, whereas reducing the protein expression and promoter activity of MUC1. A greater effect was observed in the presence of metformin. In addition, solamargine reduced NF-κB subunit p65 protein expression. Exogenously expressed p65 resisted solamargine-reduced MUC1 protein and promoter activity. Interestingly, exogenously expressed MUC1 attenuated solamargine-stimulated phosphorylation of AMPKα and, more importantly reversed solamargine-inhibited cell growth. Finally, solamargine increased phosphorylation of AMPKα, while inhibiting MUC1, p65 and tumor growth were observed in vivo. Overall, our results show that solamargine inhibits the growth of CRPC cells through AMPKα-mediated inhibition of p65, followed by reduction of MUC1 expression in vitro and in vivo. More importantly, metformin facilitates the antitumor effect of solamargine on CRPC cells.

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“…Studies have demonstrated that persistent AR signalling remains the key driver in the progression to CRPC, and AR down-regulation is considered a preventive strategy for prostate cancer [63]. Metformin has been shown to reduce AR protein levels in a dose-dependent manner in androgen receptor-positive cell lines [49], and repress the AR signalling pathway via down-regulation of AR mRNA [64], again supporting a potential role for metformin in combination with ADT therapy.…”

Section: Biological Effectsmentioning

confidence: 99%

Metformin and Prostate Cancer: a New Role for an Old Drug

2017

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Purpose of ReviewSince epidemiological studies first demonstrated a potential positive effect of metformin in reducing cancer incidence and mortality, there has been an increased interest in not only better understanding metformin’s mechanisms of action but also in exploring its potential anti-cancer effects. In this review, we aim to summarise the current evidence exploring a role for metformin in prostate cancer therapy.Recent FindingsPreclinical studies have demonstrated a number of antineoplastic biological effects via a range of molecular mechanisms. Data from retrospective epidemiological studies in prostate cancer has been mixed; however, there are several clinical trials currently underway evaluating metformin’s role as an anti-cancer agent. Early studies have shown benefits of metformin to inhibit cancer cell proliferation and improve metabolic syndrome in prostate cancer patients receiving androgen deprivation therapy (ADT).SummaryWhile the body of evidence to support a role for metformin in prostate cancer therapy is rapidly growing, there is still insufficient data from randomised trials, which are currently still ongoing. However, evidence so far suggests metformin could be a useful adjuvant agent, particularly in patients on ADT.

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Metformin represses androgen‐dependent and androgen‐independent prostate cancers by targeting androgen receptor

Cited by 57 publications

References 23 publications

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

Metformin and Prostate Cancer: a New Role for an Old Drug

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