Resveratrol attenuates constitutive STAT3 and STAT5 activation through induction of PTPε and SHP-2 tyrosine phosphatases and potentiates sorafenib-induced apoptosis in renal cell carcinoma

BMC Nephrology

Research Article

Sang Hyun Baek¹  Bum Sang Shim¹  Jae-Young Um¹  Kwang Seok Ahn¹  Chulwon Kim¹ 

[1] Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemungu, 130-701, Seoul, Republic of Korea;

关键词: Resveratrol;    STAT3/5;    PTPε;    SHP-2;    Renal cell carcinoma;   

DOI  :  10.1186/s12882-016-0233-7

 received in 2015-07-01, accepted in 2016-02-19,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundSignal transducers and activators of transcription (STAT) proteins are critical transcription factor that are aberrantly activated in various types of malignancies, including renal cell carcinoma (RCC).MethodsWe investigated the effect of resveratrol (RES), an edible polyphenol phytoalexin on STAT3 and STAT5 activation cascade in both Caki-1 and 786-O RCC cell lines.ResultsWe found that RES suppressed both constitutive STAT3 (tyrosine residue 705 and serine residue 727) and STAT5 (tyrosine residue 694 and 699) activation, which correlated with the suppression of the upstream kinases (JAK1, JAK2, and c-Src) in RCC. Also, RES abrogated DNA binding capacity and nuclear translocation of these two transcription factors. RES-induced an increased expression of PTPε and SHP-2 and the deletion of these two genes by small interfering RNA abolished the ability of RES to inhibit STAT3 activation, suggesting the critical role of both PTPε and SHP-2 in its possible mechanism of action. Moreover, RES induced S phase cell cycle arrest, caused induction of apoptosis, loss of mitochondrial membrane potential, and suppressed colony formation in RCC. We also found that RES downregulated the expression of STAT3/5-regulated antiapoptotic, proliferative, and metastatic gene products; and this correlated with induction of caspase-3 activation and anti-invasive activity. Beside, RES potentiated sorafenib induced inhibitory effect on constitutive STAT3 and STAT5 phosphorylation, apoptotic effects in 786-O cells, and this correlated with down-regulation of various oncogenic gene products.ConclusionOverall, our results suggest that RES is a blocker of both STAT3 and STAT5 activation and thus may exert potential growth inhibitory effects against RCC cells.

【 授权许可】

CC BY   
© Kim et al. 2016