Aspirin is a novel chemopreventive agent against malignancy. However, outcomes of aspirin monotherapy of renal cell carcinoma (RCC) are inconsistent across studies. ABT-737, an BH3 mimetic inhibitor, is also a promising antitumor drug. Cancer cells including those from RCC, that have high levels of Mcl-1, are refractory to ABT-737-induced apoptosis. We here investigated how aspirin treatment modulates the ABT-737-induced apoptosis. Using the in vitro model of human 786-O cells, we showed that aspirin had sensitized cells to ABT-737 induced apoptosis. Such aspirin-induced changes of ABT-737 resistance was accompanied by a host of biochemical events like protein phosphatase 2A (PP2A) activation, AKT dephosphorylation, Mcl-1/FLICE inhibiting protein (FLIP)/XIAP downregulation, and Bax mitochondrial redistribution. The PP2A inhibitor, okadaic acid, was able to reverse the apirin-induced apoptotic changes. Apart from the aspirin treatment, Mcl-1 silencing also rendered cells vulnerable to ABT-737 induced apoptosis. Since PP2A, Akt, and Mcl-1 play critical roles in RCC malignancy and treatment resistance, our present study showed that aspirin, an alternative adjuvant agent, had recalled ABT-737 sensitivity in the RCC cells through processes involving the PP2A/Akt/Mcl-1 axis.
Biochemical and biophysical research communications. 2018 May 21 [Epub ahead of print]
Yen-Chuan Ou, Jian-Ri Li, Jiaan-Der Wang, Wen-Ying Chen, Yu-Hsiang Kuan, Ching-Ping Yang, Su-Lan Liao, Hsi-Chi Lu, Chun-Jung Chen
Department of Urology, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan., Division of Urology, Taichung, Taiwan., Department of Pediatrics & Child Health Care, Taichung Veterans General Hospital, Taichung, Taiwan., Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan., Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan., Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan., Food Science Department and Graduate Institute, Tunghai University, Taichung, Taiwan., Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan. Electronic address: .