Metformin’s action on cancer

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Recent prospective and case-control studies conducted on large cohorts have confirmed that T2D is associated with significantly increased risk of cancer mainly affecting breast, colon, prostate, kidney and pancreas [103]. This increased risk has been attributed to the growth-promoting effect of chronic elevated plasma insulin levels [104]. Insulin resistance and resultant hyperinsulinemia might indeed promote carcinogenesis directly through the insulin receptor or indirectly by increasing the levels of insulin-like growth factors (IGF), steroid sex hormones, inflammatory processes and disrupting adipokines homeostasis [104]. However, additional explanations for this association may be invoked such as the role of persistent elevated plasma glucose levels [105]. Given the epidemiological evidence between T2D and increased risk of cancer, the impact of metformin therapy on cancer risks and cancer-related mortality has been evaluated in a first pilot case-control study with a cohort of 12000 T2D patients [106]. Metformin therapy was associated with a reduced risk of cancer (odds-ratio of any exposure to metformin was 0.79). Furthermore, the authors found a dose-response relationship between duration of exposure to metformin and cancer incidence [106]. Similarly, more recent retrospective and observational studies reported reduced incidence of neoplastic diseases and cancer mortality in T2D patients treated with metformin [107-109]. Importantly, metformin use has been associated with a significant decrease in the relative risk of specific cancers, such as prostate, pancreas and breast cancers [110-112]. These observations are consistent with in vitro and in vivo studies showing antiproliferative action of metformin on various cancer cell lines [113] and several cancers in animal models (Table 1).

Although the underlying mechanisms are not yet completely elucidated, the association between metformin and reduced risk of cancer in T2D patients may be simply explained through metformin action on improvement of blood glucose and insulin levels [114]. Accordingly, prevention of tumor growth in animal models with diet-induced hyperinsulinemia is attributable to reductions in circulating insulin levels [115, 116]. Given that hyperinsulinemia is associated with increased levels of IGF-1, it is possible that the metformin-lowering effects on serum insulin and IGF-1 levels might explain, at least in part, its therapeutic efficacy (Figure 3). This hypothesis is particularly relevant in light of recent studies showing that calorie restriction, which lowers insulin and IGF-1 levels, induces a dramatic decrease in the incidence of cancer in rodent models [117]. However, a decrease in insulinemia is not always correlated with metformin efficacy as shown in PTEN^+/-, HER-2/neu and APC^min/+ mouse tumor models, indicating an insulin-independent antitumoral action of metformin [118-120]. Hence, metformin appears to have a direct action on tumor growth both in vitro and in vivo by a mechanism involving activation of the LKB1/AMPK pathway and subsequent modulation of downstream pathways controlling cellular proliferation (Figure 3). AMPK knock-down by siRNA or AMPK inhibitors partially revert the antiproliferative action of metformin in breast and ovarian cancer cells [121-123]. Furthermore, antitumoral action of metformin was significantly reduced in mice displaying a reduction in LKB1 expression [119]. The antineoplastic activity of metformin via AMPK activation is mediated through the inhibition of mTORC1 signaling, leading to inhibition of protein synthesis and cell proliferation [121, 123, 124]. AMPK inhibits mTORC1 at multiple levels through the phosphorylation of tuberous sclerosis 2 protein (TSC2) on Ser¹³⁴⁵, leading to accumulation of Rheb-GDP (the inactive form), and the phosphorylation of raptor on Ser⁷²² and Ser⁷⁹², which disrupts its association with mTOR and thereby prevents mTORC1 activation. However, recent studies revealed the existence of an alternative AMPK-independent pathway, potentially mediated by RAG GTPase, by which metformin inhibits mTORC1 signaling [125]. Of particular note is the inhibition of IGF-1-induced mTOR activity by thiazolidinediones, another class of antidiabetic drugs which activated AMPK [18], indicating that activation of the kinase could further attenuate signaling pathways downstream insulin and/or IGF-1 receptors, particularly at the level of mTOR [126]. Furthermore, it is of interest that metformin-induced activation of AMPK disrupted crosstalk between insulin/IGF-1 and G-protein-coupled receptor signaling pathways in pancreatic cancer cells [127]. Another mode of action of metformin might be through an AMPK-mediated regulation of fatty acid synthesis. Indeed, cells derived from prostate, breast and colon cancers constitutively over-express fatty acid synthase (FAS), a key enzyme for de novo fatty acid biosynthesis, which has been associated with the malignant phenotype. Interestingly, it has been observed that reduction of FAS and ACC expression by AMPK activation diminishes the viability and growth of prostate cancer cells [128]. Another potential mechanism is based on the positive impact of metformin on chronic inflammation [129], a major contributory factor to cancer development and progression. Emerging results showing the capacity of AMPK to inhibit the inflammatory responses [130] suggest that metformin may also target the inflammatory component present in the microenvironment of most neoplastic tissues, leading to tumor reduction. In addition, inhibition of neoplastic angiogenesis by metformin might also participate in the reduction of tumor growth [131]. Consistently, metformin has been shown to significantly decrease the levels of vascular endothelial growth factor (VEGF) and PAI-1 [132].

Although these results suggest a pivotal role of LKB1/AMPK signaling, the antineoplastic action of metformin could also be independent of AMPK activation. Indeed,  metformin was reported to decrease the expression of the oncoprotein HER2 (erbB-2) in human breast cancer cells via a direct and AMPK-independent inhibition of p70S6K1 activity [133]. Metformin also exerts is anti-cancer effect through induction of cell-cycle arrest in prostate cancer cell lines via a decrease in cyclin D1 protein expression [134] and an increase in REDD1 expression in a p53-dependent manner [135]. In breast cancer cells, metformin-induced cell-cycle arrest is due to enhanced binding of CDK2 by p27Kip or p21Cip in addition to cyclin D1 downregulation and AMPK activation [136]. In addition to the inhibition of cancer cells proliferation, metformin has been shown to promote cell death of some cancer cells through activation of apoptotic pathways by both caspase-dependent and caspase-independent mechanisms [137, 138]. The caspase-independent pathway involved activation of poly(ADP-ribose) polymerase (PARP) and correlates with enhanced synthesis of PARP and nuclear translocation of apoptosis-inducing factor (AIF), which plays an important role in mediating cell death [139]. Additionally, it was showed that metformin-stimulated apoptosis of colon cancer cells was associated with loss of p53-dependent enhancement of autophagy and glycolysis, an effect stimulated by nutrient deprivation. In contrast, metformin promotes apoptosis of prostate cancer cells in a p53-dependent manner in the presence of 2-deoxyglucose [140].

Metabolic adaptations are critical to maintain survival of cancer cells that are often under a variety of stress stimuli, such as hypoxia and lack of nutrients. To successfully meet their high metabolic demand, it is crucial that cancer cells engage proper adaptive responses to provide sufficient ATP supply and support survival. A recent study revealed that AMPK activation promotes the survival of cells metabolically impaired by glucose limitation in part through p53 activation [141]. It has been suggested that metformin could inhibit the growth of cancer cells by decreasing cellular energy status and force a metabolic conversion that cancer cells are unable to execute. Indeed, loss of p53 impairs the ability of cancer cells to respond to metabolic changes induced by metformin and to survive under conditions of nutrient deprivation [142]. Similarly, LKB1-deficient cells were more sensitive to metformin-induced energy stress when cultured at low glucose concentration and were unable to compensate for the decreased cellular ATP concentration causing cell death [116]. A recent report demonstrated that the combination of metformin and 2-deoxyglucose inhibited mitochondrial respiration and glycolysis in prostate cancer cells leading to a massive ATP depletion and affect cell viability by inducing apoptosis [140].