In vitro and in vivo anti-melanoma action of metformin

Janjetović, Kristina; Harhaji-Trajković, Ljubica; Misirkic-Marjanovic, Maja; Vučićević, Ljubica; Stevanović, Darko; Zogović, Nevena; Šumarac-Dumanović, Mirjana; Micić, Dragan; Trajkovič, Vladimir

doi:10.1016/j.ejphar.2011.07.004

Cited by 91 publications

(88 citation statements)

References 56 publications

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“…These results were confirmed by retrospective epidemiologic studies that reported a decrease in cancer risk in patients with diabetes treated with metformin (12). In addition, metformin was reported by several groups, including ours, to inhibit melanoma cell proliferation (13)(14)(15)(16). In our previous study, we showed that metformin dramatically impairs the growth of melanoma tumors in vitro and in vivo by inducing autophagic cell death leading to massive apoptosis (13).…”

Section: Introductionsupporting

confidence: 75%

“…For this purpose, using in vitro and in vivo approaches, we and others previously showed the potent effects of the antidiabetic drug metformin on reduction of melanoma cells growth and xenograft development (13)(14)(15)(16). One crucial step of melanoma development appears to be promotion of an EMT-like transition, a process having central role during RGP and VGP progression, melanoma invasion, and metastatic dissemination of melanoma cells (19,20).…”

Section: Discussionmentioning

confidence: 99%

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Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner

Cerezo

Tichet

Abbe

et al. 2013

Molecular Cancer Therapeutics

181

139

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Metformin was reported to inhibit the proliferation of many cancer cells, including melanoma cells. In this report, we investigated the effect of metformin on melanoma invasion and metastasis development. Using different in vitro approaches, we found that metformin inhibits cell invasion without affecting cell migration and independently of antiproliferation action. This inhibition is correlated with modulation of expression of proteins involved in epithelial-mesenchymal transition such as Slug, Snail, SPARC, fibronectin, and Ncadherin and with inhibition of MMP-2 and MMP-9 activation. Furthermore, our data indicate that this process is dependent on activation of AMPK and tumor suppressor protein p53. Finally, we showed that metformin inhibits melanoma metastasis development in mice using extravasation and metastasis models. The presented data reinforce the fact that metformin might be a good candidate for clinical trial in melanoma treatment.

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Section: Introductionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner

Cerezo

Tichet

Abbe

et al. 2013

Molecular Cancer Therapeutics

181

139

View full text Add to dashboard Cite

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“…Studies have indicated that metformin efficiently suppresses the growth of various tumors, such as prostate carcinoma, and breast, lung and pancreatic cancer (11,12), which is in accordance with the results of a retrospective epidemiological study, showing a reduction in cancer risk in patients with diabetes who were receiving metformin (13). Furthermore, a number of studies have reported that metformin inhibits melanoma cell proliferation (14)(15)(16)(17).…”

Section: Introductionsupporting

confidence: 68%

“…Observations have shown that metformin affects the regulation of tumor cell proliferation, cell-cycle regulation, apoptosis and autophagy (21). It has been reported that metformin may be effective as an anticancer drug in a variety of types of tumors, such as prostate (22), breast (23), lung (24) and pancreatic cancer (25), and melanoma (15). A retrospective epidemiological study demonstrated a reduction in cancer risk in diabetic patients treated with metformin (13).…”

Section: Discussionmentioning

confidence: 99%

Metformin upregulates E-cadherin and inhibits B16F10 cell motility, invasion and migration

Liang

Ding

et al. 2015

Oncology Letters

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Abstract. Malignant melanoma is a highly metastatic cancer, and has a poor prognosis once metastasis has occurred. E-cadherin downregulation is associated with a poorer prognosis in various types of cancer, including lung, ovarian, cervical and prostate. In the majority of cancer cell lines, E-cadherin upregulation inhibits cell motility, migration and invasiveness, and reduces tumor metastasis in in vivo models. In the present study, the inhibitory effects of metformin on the motility, invasion and migration of the B16F10 murine melanoma cell line, and the possible molecular mechanisms underlying this effect were investigated. B16F10 cells were treated with various concentrations of metformin for 24 h and their motility, migration and invasion were tested using a wound-healing assay, a migration assay and a matrigel invasion assay, respectively. Furthermore, the expression of E-cadherin was measured by immunocytochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction. The results showed that metformin effectively upregulated the expression of E-cadherin, and inhibited B16F10 cell motility, migration and invasion, in a dose-dependent manner. This suggested that the inhibition of motility, migration and invasion of B16F10 cells by metformin may be associated with the upregulation of E-cadherin expression, indicating that metformin may have a role in the treatment of melanoma.

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“…Some reports suggest that metformin can activate p53 by both AMPKdependent (63,64) and independent (65,66) mechanisms to induce cell apoptosis and growth arrest and therefore may be beneficial for cancer therapy. Salicylate is an ancient cyclooxygenase inhibitor, derivatives of which have been used for treating diverse disorders (67,68).…”

Section: Discussionmentioning

confidence: 99%

AMP-Activated Protein Kinase Induces p53 by Phosphorylating MDMX and Inhibiting Its Activity

Zhang

Lee

et al. 2014

Molecular and Cellular Biology

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h AMP-activated protein kinase (AMPK) has been shown to activate p53 in response to metabolic stress. However, the underlying mechanisms remain unclear. Here we show that metabolic stresses induce AMPK-mediated phosphorylation of human MDMX on Ser342 in vitro and in cells, leading to enhanced association between MDMX and 14-3-3. This markedly inhibits p53 ubiquitylation and significantly stabilizes and activates p53. By striking contrast, no phosphorylation of MDM2 by AMPK was noted. AMPK-mediated MDMX phosphorylation, MDMX-14-3-3 binding, and p53 activation were drastically reduced in mouse embryo fibroblasts harboring endogenous MDMX with S341A (mouse homologue of human serine 342), S367A, and S402A (mouse homologue of human serine 403) mutations. Moreover, deficiency of AMPK prevented MDMX-14-3-3 interaction and p53 activation. The activation of p53 through AMPK-mediated MDMX phosphorylation and inactivation was further confirmed by using cell and animal model systems with two AMPK activators, metformin and salicylate (the active form of aspirin). Together, the results unveil a mechanism by which metabolic stresses activate AMPK, which, in turn, phosphorylates and inactivates MDMX, resulting in p53 stabilization and activation.T he p53 tumor suppressor executes its antitumor functions primarily via its transcriptional activity to induce the expression of protein-encoding genes responsible for p53-dependent apoptosis, cell growth arrest, differentiation, and senescence (1) as well as its ability to induce apoptosis and autophagy by transcriptionindependent mechanisms (2). Since these cellular functions are detrimental to cells, p53 is often tightly monitored by a pair of partner proteins, MDM2 (called HDM2 in humans) and MDMX (also called MDM4), in normally growing cells (3-5). MDM2 and MDMX act as a complex during early embryogenesis (6-10) to ubiquitylate p53 and mediate its proteosomal turnover as well as inactivate its activity in a negative-feedback fashion (10-12), and cooperatively or individually restrain the p53 level to maintain the normal development and function of different tissues (13-16), by binding to p53, inhibiting its transcriptional activity and/or enhancing its ubiquitination. Hence, to activate p53, cells need to trigger different cellular mechanisms or pathways that block the MDM2-MDMX-p53 feedback loop through modifications of one of these proteins in response to a variety of stresses (17, 18). For instance, DNA damage signals can induce p53 by activating the ATM-Chk2 or ATR-Chk1 pathway that leads to phosphorylation of p53, MDMX, and MDM2 (19-21). Of relevance to MDMX, Ser367 phosphorylation by Chk2 or Chk1 triggers interaction between MDMX and 14-3-3, leading to MDMX inactivation and p53 activation (19,21,22). The importance of 14-3-3 binding to Ser367-phosphorylated MDMX for p53 activation by DNA damage was further emphasized in an animal knock-in study in which three serines, including Ser341, Ser367, and Ser402 (23), were mutated into alanines. This mutant MDMX exhibits substantial...

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In vitro and in vivo anti-melanoma action of metformin

Cited by 91 publications

References 56 publications

Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner

Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner

Metformin upregulates E-cadherin and inhibits B16F10 cell motility, invasion and migration

AMP-Activated Protein Kinase Induces p53 by Phosphorylating MDMX and Inhibiting Its Activity

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