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 Nephrol. 2016 Feb 25;17:19. doi: 10.1186/s12882-016-0233-7.

Abstract

Background: 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).

Methods: We 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.

Results: We 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.

Conclusion: Overall, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Carcinoma, Renal Cell / drug therapy*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Membrane Potential, Mitochondrial / drug effects
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Phenylurea Compounds / pharmacology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / drug effects
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4 / drug effects
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4 / metabolism
  • Resveratrol
  • S Phase Cell Cycle Checkpoints / drug effects
  • STAT3 Transcription Factor / drug effects*
  • STAT3 Transcription Factor / metabolism
  • STAT5 Transcription Factor / drug effects*
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Sorafenib
  • Stilbenes / pharmacology*

Substances

  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Phenylurea Compounds
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • Stilbenes
  • Niacinamide
  • Sorafenib
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4
  • Resveratrol