Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer

Laskov, Ido; Drudi, Laura M.; Beauchamp, Marie‐Claude; Yasmeen, Amber; Ferenczy, Alex; Pollak, Michael; Gotlieb, Walter H.

doi:10.1016/j.ygyno.2014.06.014

Cited by 96 publications

(74 citation statements)

References 40 publications

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“…The links of AMPKα, ERK1/2 signaling to IGFBP1 expression/function have been reported [44, 45]; early study found that a pro-inflammatory cytokine IL-1β stimulated IGFBP1 synthesis through activation of MEK/ERK signaling in human hepatoma cells [44]. Also, report showed that activation of AMPK could stimulate IGFBP1 secretion, thereby overcoming the inhibitory effect of insulin in rat hepatoma cells [46].…”

Section: Discussionmentioning

confidence: 99%

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Tang¹,

Wu²,

Zheng³

et al. 2017

Cell Physiol Biochem

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Background: Emodin has anti-neoplastic activities on multiple tumors. However, the molecular mechanisms underlying this effect still remain to be fully understood. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays and flow cytometry, respectively. Cell invasion and migration were examined by transwell invasion and wound healing assays. Western blot analysis was performed to examine the phosphorylation and protein expression of AMP-activated protein kinase alpha (AMPKα), extracellular signaling-regulated kinase 1/2 (ERK1/2), peroxisome proliferators-activated receptor gamma (PPARγ), insulin-like growth factor (IGF) binding protein 1 (IGFBP1) and the transcription factor Sp1. QRT-PCR was used to examine the mRNA levels of the IGFBP1 gene. Small interfering RNAs (siRNAs) were used to knockdown PPARγ and IGFBP1 genes. Exogenously expression of IGFBP1 and Sp1 was determined by transient transfection assays. IGFBP1 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. In vivo nude mice xenograft model and bioluminescent imaging system were used to confirm the findings. Results: We showed that emodin induced cell cycle arrest of NSCLC cells. Emodin increased PPARγ protein and luciferase reporter activity, which were abolished by inhibitors of MAPK extracellular signaling-regulated kinase (ERK) kinase (MEK)/ERK and AMPK. Silencing of PPARγ abrogated emodin-inhibited cell growth and cell cycle arrest. Furthermore, emodin elevated IGFBP1 mRNA, protein, and promoter activity through activation of PPARγ. Intriguingly, overexpressed Sp1 attenuated emodin-induced IGFBP1 expression, which was not observed in cells with silenced PPARγ gene. Moreover, silencing of IGFBP1 gene blunted emodin-induced inhibition of cell growth and cell cycle arrest. On the contrary, overexpressed IGFBP1 enhanced emodin-induced phosphorylation of AMPKα and ERK1/2, and restored emodin-inhibited growth in cells with silenced endogenous IGFBP1 gene. Emodin also inhibited growth of lung xenograft tumors and Sp1, and increased IGFBP1 and PPARγ protein expressions In vivo. Conclusion: Collectively, our results show that emodin inhibits growth of non-small-cell lung cancer (NSCLC) cells through ERK and AMPKα-mediated induction of PPARγ, followed by reduction of Sp1. This in turn induces IGFBP1 gene expression. Thus, the signaling cascades, positive feedback loop and cooperative interplay between transcription factors-induced the expression of IGFBP1 gene contribute to the overall responses of emodin. This study provides a novel mechanism by which emodin inhibits growth of human lung cancer cells.

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Section: Discussionmentioning

confidence: 99%

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Tang¹,

Wu²,

Zheng³

et al. 2017

Cell Physiol Biochem

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“…27 Metformin's immediate downstream target is AMPK, and AMPK activation leads to regulation of multiple downstream pathways involved in the control of cellular proliferation, including the mTOR pathway. Metformin has a direct action that inhibits cell proliferation through activation of AMPK and resultant inhibition of mTOR and its effector.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor 1/Mammalian Target of Rapamycin and AMP-Activated Protein Kinase Signaling Involved in the Effects of Metformin in the Human Endometrial Cancer

Cai

Sun

et al. 2016

Int J Gynecol Cancer

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“…As indicated earlier, metformin treatment enhances insulin sensitivity, induces glycolysis, and suppresses hepatic gluconeogenesis. There is some evidence that metformin may also have cardioprotective effects (Eurich et al 2013;Hong et al 2013) and contribute to the prevention of some forms of human cancer (Cazzaniga et al 2013;Anisimov 2014;Laskov et al 2014). This therapeutic profile of metformin supports its use for age-related diseases and longevity.…”

Section: Metformin As An Anti-aging Drugmentioning

confidence: 99%

Metformin: A Hopeful Promise in Aging Research

Novelle

Ali

Diéguez

et al. 2016

Cold Spring Harb Perspect Med

131

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Even though the inevitable process of aging by itself cannot be considered a disease, it is directly linked to life span and is the driving force behind all age-related diseases. It is an undisputable fact that age-associated diseases are among the leading causes of death in the world, primarily in industrialized countries. During the last several years, an intensive search of antiaging treatments has led to the discovery of a variety of drugs that promote health span and/or life extension. The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer, inflammation, and agerelated pathologies. Here, we summarize the recent developments about metformin use in translational aging research and discuss its role as a potential geroprotector.

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Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer

Cited by 96 publications

References 40 publications

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Insulin-Like Growth Factor 1/Mammalian Target of Rapamycin and AMP-Activated Protein Kinase Signaling Involved in the Effects of Metformin in the Human Endometrial Cancer

Metformin: A Hopeful Promise in Aging Research

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