Metformin Inhibites Diabetic Renal Cell Carcinoma Via Promoting Autophagy And Inducing Apoptosis

Objective: Effective therapies for early renal cell carcinoma(RCC)usually involve surgical excision.Currently no standard effective drug therapy for RCC is available.Type 2 diabetes mellitus(T2DM)increases the incidence and mortality of RCC.It is thus necessary to find a therapy that can help improve diabetes control and reduce the incidence of cancer simultaneously.Methods:(1)Fresh RCC tissues from 12 RCC patients(with or without T2DM)were collected.Autophagy related proteins,IGF-1 and IGF-1R were evaluated in human RCC tissues.Besides,another 14 RCC patients(with or without T2DM)were selected,these patients’ paraffin-embedded tissues and related clinical pathological data were also collected.The expression of LC3 B was measured by immunofluorescence.These patients were divided into two groups,the RCC patients without T2 DM is the first group(RCC+DM-);the other RCC patients with T2 DM is the second group(RCC+DM+).(2)In vitro,the RCC cell lines 786-O and OS-RC-2 were used as cell model.Electron microscope,flow cytometry,molecular experiment were used to explore the effect of metformin on cell proliferation,apoptosis and autophagy with or without the exist of diabetic microenvironment.Results: Decreased expression of the autophagy-related protein LC3 B and increased expression of IGF-1 and IGF-1R were detected in human RCC tissues of T2 DM patients than those without T2 DM.Importantly,metformin treatment increased autophagy and induced growth inhibition and apoptosis in RCC cells.Meanwhile,decreased phosphorylation of signal transducer and activator of transcription 3(STAT3)and Bcl-2 expression were found following metformin treatment.Furthermore,metformin counteracted diabetic environment-induced growth acceleration and down-regulation of autophagy in RCC cells via the inactivation of the STAT3/Bcl-2pathway.Conclusions: In this research,increased IGF-1 expression and inhabited autophagy level were observed in human RCC tissues with or without T2 DM.In RCC cells,we indicated that IGF-1 could active STAT3 signaling,promoted RCC cell proliferation,and induced autophagy inhibition;whereas,metformin triggered growth inhibition and autophagic cell death via the inactivation of STAT3/Bcl-2 pathway.Thus,metformin counteracted IGF-1-induced growth acceleration and down-regulation of autophagy in RCC cells via the inactivation of the STAT3/Bcl-2 pathway.Above all,we suggested metformin inhibites diabetic renal cell carcinoma via promoting autophagy and inducing apoptosis.