Metformin Is an AMP Kinase–Dependent Growth Inhibitor for Breast Cancer Cells

Zakikhani, Mahvash; Dowling, Ryan J.O.; Fantus, I. George; Sonenberg, Nahum; Pollak, Michael

doi:10.1158/0008-5472.can-06-1500

Cited by 951 publications

(536 citation statements)

References 23 publications

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“…These results are emphasized by the fact that the antidiabetic drug inhibited S6K1 phosphorylation in the absence of the two catalytic units of AMPK suggesting that the antiproliferative effect of metformin are mediated through the mTOR pathway independently of AMPK. Our study contradicts the results obtained in MCF-7 by Zakikhani et al (2006) who showed that metformin inhibits cell growth via the a1 AMPK subunit in MCF-7 breast cancer cells. This disparity may be due to a cell specific effect.…”

Section: Discussioncontrasting

confidence: 99%

“…Recent data suggest that metformin could protect from cancer (Schneider et al, 2001;Evans et al, 2005) and inhibit breast and glial cancer cell proliferation in vitro (Zakikhani et al, 2006). Here we show that metformin not only is a very potent inhibitor of human prostate cancer cell growth, but also inhibits tumorigenesis in a xenograft model when it is administrated orally or i.p.…”

Section: Discussionmentioning

confidence: 49%

“…Furthermore, AMPK activation has been shown to inhibit the mTOR pathway and S6K1 phosphorylation implicated in protein synthesis suggesting that this pathway may regulate cell proliferation. Recently, Zakikhani et al (2006) showed that metformin inhibits MCF7 cancer cell growth in vitro and this effect was reverted by AMPK knock-down. However, the cellular mode of action and the cellular targets of metformin in cancer cells remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

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Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G 0 /G 1 . This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27 kip protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

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The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

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“…It will be of interest to determine whether this protective effect of Lkb1-AMPK signaling involves systemic metabolic effects, metabolic effects in evolving tumor cells, maintenance of cell polarity, or a combination of these processes. Recent data suggest that this pharmacological activation of AMPK may also be beneficial for treatment of established tumors with intact Lkb1-AMPK-TSC signaling, as metformin slows proliferation of cancer cell lines (Zakikhani et al, 2006).…”

Section: Mechanisms Of Neoplastic Suppressionmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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“…In addition, an AMPK-independent, rag GTPasedependent pathway by which metformin inhibits mammalian target of rapamycin complex 1 has recently been described (Kalender et al, 2010). By decreasing mitochondrial ATP production, metformin can indirectly activate LKB1-AMPK signaling in vitro in transformed cells, with consequences including inhibition of protein synthesis (Dowling et al, 2007), proliferation (Zakikhani et al, 2006 and expression of fatty acid synthase (Algire et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

et al. 2010

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Hypothesis-generating epidemiological research has suggested that cancer burden is reduced in diabetics treated with metformin and experimental work has raised questions regarding the role of direct adenosine monophosphate-activated protein kinase (AMPK)-mediated antineoplastic effects of metformin as compared with indirect effects attributable to reductions in circulating insulin levels in the host. We treated both tumor LKB1 expression and host diet as variables, and observed that metformin inhibited tumor growth and reduced insulin receptor activation in tumors of mice with diet-induced hyperinsulinemia, independent of tumor LKB1 expression. In the absence of hyperinsulinemia, metformin inhibited only the growth of tumors transfected with short hairpin RNA against LKB1, a finding attributable neither to an effect on host insulin level nor to activation of AMPK within the tumor. Further investigation in vitro showed that cells with reduced LKB1 expression are more sensitive to metformin-induced adenosine triphosphate depletion owing to impaired ability to activate LKB1-AMPK-dependent energy-conservation mechanisms. Thus, loss of function of LKB1 can accelerate proliferation in contexts where it functions as a tumor suppressor, but can also sensitize cells to metformin. These findings predict that any clinical utility of metformin or similar compounds in oncology will be restricted to subpopulations defined by host insulin levels and/or loss of function of LKB1.

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Metformin Is an AMP Kinase–Dependent Growth Inhibitor for Breast Cancer Cells

Cited by 951 publications

References 23 publications

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

LKB1; linking cell structure and tumor suppression

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

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