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.
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2017 Dec 11 [Epub ahead of print]
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
College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: ., College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: ., School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: ., College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: ., Division of Pediatric Infectious Disease, Department of Pediatrics, E-Da Hospital/I-Shou University, Kaohsiung 84001, Taiwan. Electronic address: ., Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: ., College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: ., Department of Pediatrics, E-DA Hospital, I-Shou University, Kaohsiung 84001, Taiwan. Electronic address: ., College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan; Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA. Electronic address: ., Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA; Albany Medical College, Albany, NY 12208, USA. Electronic address: .