Resveratrol induces sumoylated COX-2-dependent anti-proliferation in human prostate cancer LNCaP cells.

Abstract

Cyclooxygenase (COX)-2 has been implicated in cancer development. However, resveratrol-induced nuclear accumulation of COX-2 enhances p53-dependent anti-proliferation in different types of cancers. Treatment with resveratrol leads to phosphorylation and nuclear translocation of mitogen-activated protein kinase (ERK1/2), and accumulation of nuclear COX-2 to complex with pERK1/2 and p53. The consequence is Ser-15 phosphorylation of p53 (pSer15-p53), and induction of anti-proliferation in cancer cells. We investigated the mechanisms by which resveratrol-inducible COX-2 facilitates p53-dependent anti-proliferation in prostate cancer LNCaP cells. Resveratrol treatment caused nuclear accumulation and complexing of ERK1/2, pSer15-p53 and COX-2 which was activated ERK1/2-dependent. Knockdown of SUMO-1 by shRNA also reduced nuclear accumulation of COX-2. Inhibition of nuclear accumulation by the COX-2 specific inhibitor, NS-398, inhibited co-localization of nuclear COX-2 and SUMO-1. Similar results were observed in the PD98059-treated cells. Finally, inhibition of SUMO-1 expression also reduced resveratrol-induced expression of pro-apoptotic genes but increased the expression of proliferative genes. In summary, these results demonstrate that inducible COX-2 associates with phosphorylated ERK1/2 to induce the phosphorylation of Ser-15 in p53 and then complexes with p53 and SUMO-1 which binds to p53-responsive pro-apoptotic genes to enhance their expression. The inhibition of COX-2 expression and activity significantly blocks the pro-apoptotic effect of resveratrol.

• Authors: Tsai-Mu Cheng, Yu-Tang Chin, Yih Ho, Yi-Ru Chen, Yung-Ning Yang, Yu-Chen Yang, Ya-Jang Shih, Ting-I Lin, Hung-Yun Lin, Paul J Davis
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 112 Pg. 67-75 (Feb 2018) ISSN: 1873-6351 [Electronic] England
• PMID: 29242151 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• RNA, Small Interfering
• SUMO-1 Protein
• Stilbenes
• TP53 protein, human
• Tumor Suppressor Protein p53
• Cyclooxygenase 2
• Resveratrol

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (genetics)
• Blotting, Western
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (biosynthesis, metabolism)
• Enzyme Induction
• Gene Knockdown Techniques
• Humans
• MAP Kinase Signaling System
• Male
• Microscopy, Confocal
• Phosphorylation
• Prostatic Neoplasms (enzymology, pathology)
• Protein Transport
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Resveratrol
• SUMO-1 Protein (genetics, metabolism)
• Stilbenes (pharmacology)
• Sumoylation
• Tumor Suppressor Protein p53 (metabolism)