Metformin inhibits epithelial–mesenchymal transition in prostate cancer cells: Involvement of the tumor suppressor miR30a and its target gene SOX4

Zhang, Jing; Shen, Chengde; Wang, Lin; Ma, Quanping; Xia, Pingtian; Qi, Mei; Yang, Muyi; Han, Bo

doi:10.1016/j.bbrc.2014.08.154

Cited by 72 publications

(74 citation statements)

References 23 publications

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“…Its effect was first described in tissue fibrosis, where opposite effects were reported (Wang et al, 2010;Lee et al, 2013). Several studies have shown that AMPK inhibits cancer EMT, which could occur through different mechanisms (Chou et al, 2014;Zhang et al, 2014;Zhao et al, 2014). Our study using BEAS-2B cells clearly demonstrates that inhibition of TGF-b action is one of the mechanisms.…”

Section: Discussionsupporting

confidence: 56%

“…AMPK has been recently documented to be involved in EMT (Cufi et al, 2010;Vazquez-Martin et al, 2010;Wang et al, 2010Wang et al, , 2014Lee et al, 2013;Chou et al, 2014;Zhang et al, 2014). Its effect was first described in tissue fibrosis, where opposite effects were reported (Wang et al, 2010;Lee et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, AMPK inhibits cancer cell migration and EMT via both TGF-b-dependent and -independent mechanisms (Cufi et al, 2010;Xiao et al, 2010;Lim et al, 2012;Chou et al, 2014;Wang et al, 2014;Zhang et al, 2014;Thakur et al, 2015;Yan et al, 2015). With regard to AMPK regulation of the TGF-b signaling pathway, the mechanism is not clear.…”

Section: Introductionmentioning

confidence: 99%

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AMPK Inhibits the Stimulatory Effects of TGF-βon Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition

Lin¹,

Li²,

He³

et al. 2015

Mol Pharmacol

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AMP-activated protein kinase (AMPK), an important downstream effector of the tumor suppressor liver kinase 1 (LKB1) and pharmacologic target of metformin, is well known to exert a preventive and inhibitory effect on tumorigenesis; however, its role in cancer progression and metastasis has not been well characterized. The present study investigates the potential roles of AMPK in inhibiting cancer-cell migration and epithelialto-mesenchymal transition (EMT) by regulating the canonical transforming growth factor b (TGF-b) signaling pathway, an important promoting factor for cancer progression. Our results showed that activation of AMPK by metformin inhibited TGF-binduced Smad2/3 phosphorylation in cancer cells in a dosedependent manner. The effect of metformin is dependent on the presence of LKB1. A similar effect was obtained by expressing a constitutive active mutant of AMPKa1 subunit, whereas the expression of a dominant negative mutant of AMPKa1 or ablation of AMPKa subunits greatly enhanced TGF-b stimulation of Smad2/3 phosphorylation. As a consequence, expression of genes downstream of Smad2/3, including plasminogen activator inhibitor-1, fibronectin, and connective tissue growth factor, was suppressed by metformin in a LKB1-dependent fashion. In addition, metformin blocked TGF-b-induced inteleukin-6 expression through both LKB1-dependent and -independent mechanisms. Our results also indicate that activation of LKB1/AMPK inhibits TGF-b-stimulated cancer cell migration. Finally, TGF-b induction of EMT was inhibited by phenformin and enhanced by knockdown of LKB1 expression with shRNA. Together, our data suggest that AMPK could be a drug target for controlling cancer progression and metastasis.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

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AMPK Inhibits the Stimulatory Effects of TGF-βon Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition

Lin¹,

Li²,

He³

et al. 2015

Mol Pharmacol

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“…28) A recent study showed that metformin inhibited epithelial-mesenchymal transition in prostate cancer cells via upregulation of miR30a and down regulation of SOX4. 29) Metformin was also shown to enhance the antiproliferative and apoptotic effects of the androgen receptor inhibitor bicalutamide in prostate cancer. 30) In the present study, we found that metformin alone had a moderate effect on NF-κB activity.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

Wang

Huang

Zhang

et al. 2017

Biological & Pharmaceutical Bulletin

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Metformin is a commonly used drug for the treatment of type II diabetes and atorvastatin is the most prescribed cholesterol-lowering statin. The present study investigated the effects and mechanisms of metformin and atorvastatin in combination on human prostate cancer cells cultured in vitro and grown as xenograft tumor in vivo. Metformin in combination with atorvastatin had stronger effects on growth inhibition and apoptosis in PC-3 cells than either drug alone. The combination also potently inhibited cell migration and the formation of tumorspheres. Metformin and atorvastatin in combination had a potent inhibitory effect on nuclear factor-kappaB (NF-κB) activity and caused strong decreases in the expression of its downstream anti-apoptotic gene Survivin. Moreover, strong decreases in the levels of phospho-Akt and phosphorextracellular signal-regulated kinase (Erk)1/2 were found in the cells treated with the combination. The in vivo study showed that treatment of severe combined immunodeficient (SCID) mice with metformin or atorvastatin alone resulted in moderate inhibition of tumor growth while the combination strongly inhibited the growth of the tumors. Results of the present study indicate the combination of metformin and atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer and should be evaluated clinically.Key words prostate cancer; atorvastatin; metformin; apoptosis; combination Prostate cancer is one of the common types of malignant disease in males in the world and is the second leading cause of cancer-related death in the United States. The American Cancer Society estimates for 2016 approximately 180890 new cases will be diagnosed and 26120 men will die of the disease, accounting for about 8.3% of male cancer-related deaths. 1)Androgen deprivation therapy is an effective treatment for advanced prostate cancer. Unfortunately, almost all patients treated with androgen deprivation therapy will progress to castration-resistant prostate cancer (CRPC).2,3) Docetaxel is the most commonly prescribed first-line chemotherapy for CRPC. 4) Although docetaxel provides a modest (2.4-month) increase in median overall survival, many patients with CRPC cannot tolerate this cytotoxic chemotherapy due to advanced age, medical comorbidities, or limited bone marrow reserves. 5)Therefore, the identification of an effective alternative therapy with less toxicity may lead to increased survival and an improved QOL.Metformin is a well-established agent for the treatment of type II diabetes. In addition to its efficacy in lowering glucose levels, recent reports indicate it may have antitumor effects in various cancers, including prostate cancer. 6) Diabetic patients receiving metformin have been shown to have a reduced cancer incidence and a decrease in cancer-specific mortality.7) Further, epidemiologic evidence revealed a decreased incidence of prostate cancer in men taking metformin, 8,9) and both animal and in vitro models demonstrate its activity in prostate cancer cell lines. 10,11) Finall...

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“…As increased insulin levels and obesity are adverse prognostic factors for some cancer types, the lowering effects of metformin on insulin levels may play a major role in its anticancer activity (Dowling et al, 2011). Zhang et al (2014) investigated the effects of metformin on epithelial-mesenchymal transition (EMT) that has an important role in cancer progression, metastasis in prostate cancer cells and microRNA (miRNA)-based mechanisms. It was reported that metformin inhibits EMT, downregulates SOX4 (a 47 kDa protein overexpressed in prostate cancer) and upregulates tumor suppressor miR30a.…”

Section: Metformin and Cancermentioning

confidence: 99%

Microparticulate and nanoparticulate drug delivery systems for metformin hydrochloride

Çetin

Şahin

2015

Drug Delivery

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Context: Metformin hydrochloride is a biguanide derivative widely used for the treatment of type 2 diabetes, prescribed nearly to 120 million people worldwide. Metformin has a relatively low oral bioavailability (about 50-60%). Although the major effect of metformin is to decrease hepatic glucose output as an antihyperglycemic agent, its inhibitory effects on the proliferation of some cancer cells (e.g. prostate, breast, glioma cells) have been demonstrated in the cell culture studies. Development of novel formulation (e.g. microparticles, nanoparticles) strategies for metformin might be useful to improve its bioavailability, to reduce the dosing frequency, to decrease gastrointestinal side effects and toxicity and to be helpful for effective use of metformin in cancer treatment. Objective: The main aim of this review is to summarize metformin HCl-loaded micro-and nanoparticulate drug delivery systems. Method: The literature was rewieved with regard to the physicochemical, pharmacological properties of metformin, and also its mechanism of action in type 2 diabetes and cancer. In addition, micro-and nanoparticulate drug delivery systems developed for metformin were gathered from the literature and the results were discussed. Conclusion: Metformin is an oral antihyperglycemic agent and also has potential antitumorigenic effects. The repeated applications of high doses of metformin (as immediate release formulations) are needed for an effective treatment due to its low oral bioavailability and short biological half-life. Drug delivery systems are very useful systems to overcome the difficulties associated with conventional dosage forms of metformin and also for its effective use in cancer treatment.

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Metformin inhibits epithelial–mesenchymal transition in prostate cancer cells: Involvement of the tumor suppressor miR30a and its target gene SOX4

Cited by 72 publications

References 23 publications

AMPK Inhibits the Stimulatory Effects of TGF-βon Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition

AMPK Inhibits the Stimulatory Effects of TGF-βon Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

Microparticulate and nanoparticulate drug delivery systems for metformin hydrochloride

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