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.

Chulwon Kim,Kwang Seok Ahn,Bum Sang Shim,Jae-Young Um,Sang Hyun Baek

doi:10.1186/s12882-016-0233-7

Abstract

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.

Highlights

Signal 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)
RES down-regulates constitutive STAT3 and STAT5 phosphorylation in renal cell carcinoma We first tested whether RES inactivated STAT3 in Caki-1 and 786-O renal cancer cells
RES inhibits activation of upstream kinases involved in STAT3/5 signaling cascade in RCC cells In order to determine which upstream signaling molecules are involved in RES-mediated STAT3/5 inactivation, we examined the effects of RES on the phosphorylation of JAK1, JAK2, and Src in Caki-1 and 786-O cells

Summary

Introduction

Signal 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). Signal transducer and activator of transcription (STAT) proteins initially discovered as latent cytoplasmic transcription factors about two decades ago [1], consist of seven diverse members,STAT1 to STAT6, STAT5a and STAT5b [2], that have been found to play a pivotal role. Like STAT3, STAT5 has been shown to regulate proliferation and inhibition of apoptosis in several cancer cells because cyclin D1 and bcl-xL promoters contain putative STAT5 binding sites [13, 14]. Previous studies documented it has the ability to affect tumor initiation and promotion, inhibit angiogenesis and metastasis, and induce cell cycle arrest and apoptosis [24,25,26]

Objectives

Methods

Results

Discussion

Conclusion