Caveolin‐1 is essential for metformin inhibitory effect on IGF1 action in non‐small‐cell lung cancer cells

Salani, Barbara; Maffioli, Sara; Hamoudane, Meriem; Parodi, Alessia; Ravera, Silvia; Passalacqua, Mario; Alama, Angela; Nhiri, Mohamed; Cordera, Renzo; Maggi, Davide

doi:10.1096/fj.11-192088

Cited by 62 publications

(68 citation statements)

References 61 publications

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“…Although we used metformin at greater doses (400 mg/kg daily) that were reported to improve glycemic control in other models (Heishi et al, 2006;Matsumoto et al, 2008), it did not normalize glucose levels in cav-1 2/2 mice. This is consistent with reports that cav-1 is needed to mediate the acute effects of metformin on AMPK phosphorylation (Salani et al, 2012), an essential step in gluconeogenesis (Viollet et al, 2012). Also, metformin treatment did not change body weight or BP in cav-1 2/2 or WT.…”

Section: /2supporting

confidence: 92%

“…For instance, in women with polycystic ovary syndrome characterized by hyperinsulinemia, hyperandrogenism, dyslipidemia, dysadipocytokinemia, and central obesity, metformin improves cardiovascular outcomes while having minimal effects on glucose levels (Agarwal et al, 2010). Interestingly, some of the cellular actions of metformin require cav-1 (Salani et al, 2012). Thus, it is conceivable that in cav-1-deficiency states metformin may not affect glycemic control; however, whether it could still exert vascular actions under these conditions is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Dissociation of Hyperglycemia from Altered Vascular Contraction and Relaxation Mechanisms in Caveolin-1 Null Mice

Pojoga

Yao

Opsasnick

et al. 2013

J Pharmacol Exp Ther

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Hyperglycemia and endothelial dysfunction are associated with hypertension, but the specific causality and genetic underpinning are unclear. Caveolin-1 (cav-1) is a plasmalemmal anchoring protein and modulator of vascular function and glucose homeostasis. Cav-1 gene variants are associated with reduced insulin sensitivity in hypertensive individuals, and cav-1 2/2 mice show endothelial dysfunction, hyperglycemia, and increased blood pressure (BP). On the other hand, insulin-sensitizing therapy with metformin may inadequately control hyperglycemia while affecting the vascular outcome in certain patients with diabetes. To test whether the pressor and vascular changes in cav-1 deficiency states are related to hyperglycemia and to assess the vascular mechanisms of metformin under these conditions, wild-type (WT) and cav-1 2/2 mice were treated with either placebo or metformin (400 mg/kg daily for 21 days). BP and fasting blood glucose were in cav-1 2/2 . WT and did not change with metformin. Phenylephrine (Phe)-and KCl-induced aortic contraction was in cav-1 2/2 , WT; endothelium removal, the nitric-oxide synthase (NOS) blocker L-NAME (N v -nitro-L-arginine methyl ester), or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) enhanced Phe contraction, and metformin blunted this effect. Acetylcholine-induced relaxation was in cav-1 2/2 . WT, abolished by endothelium removal, L-NAME or ODQ, and reduced with metformin. Nitric oxide donor sodium nitroprusside was more potent in inducing relaxation in cav-1 2/2 than in WT, and metformin reversed this effect. Aortic eNOS, AMPK, and sGC were in cav-1 2/2 . WT, and metformin decreased total and phosphorylated eNOS and AMPK in cav-1 2/2 . Thus, metformin inhibits both vascular contraction and NO-cGMP-dependent relaxation but does not affect BP or blood glucose in cav-1 2/2 mice, suggesting dissociation of hyperglycemia from altered vascular function in cav-1-deficiency states.

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Section: /2supporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Dissociation of Hyperglycemia from Altered Vascular Contraction and Relaxation Mechanisms in Caveolin-1 Null Mice

Pojoga

Yao

Opsasnick

et al. 2013

J Pharmacol Exp Ther

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“…In mouse models, oral administration of metformin inhibits the mTOR pathway in normal lung epithelium and lung tumours by decreasing insulin and IGF1 concentrations. Metformin inhibits IGF1-induced AKT phosphorylation (Salani et al 2012). Thus, taking into account the existence of a cross-talk between AKT and mitochondria/HK2, this finding opens the possibility that metformin could drive dissociation of HK2 from mitochondria not only by a direct inhibitory effect but also by an indirect inhibitory effect ; Fig.…”

Section: Insulin Action and Metformin: A Metabolic Point Of Viewmentioning

confidence: 67%

“…While the virtual absence of OCT1 expression is associated with noncancerous tissues, tumour cells significantly express OCT1 and its downregulation limits the antineoplastic effect of metformin (Segal et al 2011, Gupta et al 2012. In this scenario, metformin's ability to increase OCT1 expression may represent an important tool for potential applications in oncology (Salani et al 2012). For instance, pyriplatin, which is a member of the platinum analogues and has never been tested in humans, provides an example of a drug distinct from metformin, for which OCT1 may play a role in its pharmacokinetic and toxicity.…”

Section: Metformin and Organic Cation Transporters In Diabetes And Camentioning

confidence: 99%

Metformin, cancer and glucose metabolism

Salani¹,

Río²,

Marini³

et al. 2014

Endocrine-Related Cancer

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104

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Metformin is the first-line treatment for type 2 diabetes. Results from several clinical studies have indicated that type 2 diabetic patients treated with metformin might have a lower cancer risk. One of the primary metabolic changes observed in malignant cell transformation is an increased catabolic glucose metabolism. In this context, once it has entered the cell through organic cation transporters, metformin decreases mitochondrial respiration chain activity and ATP production that, in turn, activates AMP-activated protein kinase, which regulates energy homeostasis. In addition, metformin reduces cellular energy availability and glucose entrapment by inhibiting hexokinase-II, which catalyses the glucose phosphorylation reaction. In this review, we discuss recent findings on molecular mechanisms that sustain the anticancer effect of metformin through regulation of glucose metabolism. In particular, we have focused on the emerging action of metformin on glycolysis in normal and cancer cells, with a drug discovery perspective.

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“…In mouse xenografts, metformin exerted comparable effects on tumor regression when it was combined with a 4-fold reduced dose of doxorubicin that is not effective as a monotherapy (14). Metformin inhibited the proliferation of NSCLC (25) and breast cancer cell lines (26), and blocked transformation in an inducible model system (27,28). These reports, together with our findings that metformin significantly enhances the effect of erlotinib and gefitinib on TKI-resistant cell lines in vitro and in vivo, suggest that metformin has the promising potential to be used as a novel anticancer agent.…”

Section: Clinical Implications Of Metformin Plus Tkis To Overcome Drumentioning

confidence: 99%

Metformin Sensitizes EGFR-TKI–Resistant Human Lung Cancer Cells In Vitro and In Vivo through Inhibition of IL-6 Signaling and EMT Reversal

Han

Xiao

et al. 2014

Clinical Cancer Research

219

183

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Purpose: The EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have become a standard therapy in patients with EGFR-activating mutations. Unfortunately, acquired resistance eventually limits the clinical effects and application of EGFR-TKIs. Studies have shown that suppression of epithelial-mesenchymal transition (EMT) and the interleukin (IL)-6/STAT3 pathway may abrogate this acquired mechanism of drug resistance of TKIs. This study aims to investigate the effect of metformin on sensitizing EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal.Experimental Design: The effect of metformin on reversing TKI resistance was examined in vitro and in vivo using MTT, BrdUrd incorporation assay, invasion assay, flow cytometry analysis, immunostaining, Western blot analysis, and xenograft implantation.Results: In this study, metformin, a widely used antidiabetic agent, effectively increased the sensitivity of TKI-resistant lung cancer cells to erlotinib or gefitinib. Metformin reversed EMT and decreased IL-6 signaling activation in TKI-resistant cells, while adding IL-6 to those cells bypassed the anti-TKI-resistance effect of metformin. Furthermore, overexpression or addition of IL-6 to TKI-sensitive cells induced TKI resistance, which could be overcome by metformin. Finally, metformin-based combinatorial therapy effectively blocked tumor growth in xenografts with TKI-resistant cancer cells, which was associated with decreased IL-6 secretion and expression, EMT reversal, and decreased IL-6-signaling activation in vivo.Conclusion: Metformin, generally considered nontoxic and remarkably inexpensive, might be used in combination with TKIs in patients with non-small cell lung cancer, harboring EGFR mutations to overcome TKI resistance and prolong survival.

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Caveolin‐1 is essential for metformin inhibitory effect on IGF1 action in non‐small‐cell lung cancer cells

Cited by 62 publications

References 61 publications

Dissociation of Hyperglycemia from Altered Vascular Contraction and Relaxation Mechanisms in Caveolin-1 Null Mice

Dissociation of Hyperglycemia from Altered Vascular Contraction and Relaxation Mechanisms in Caveolin-1 Null Mice

Metformin, cancer and glucose metabolism

Metformin Sensitizes EGFR-TKI–Resistant Human Lung Cancer Cells In Vitro and In Vivo through Inhibition of IL-6 Signaling and EMT Reversal

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