Aspirin restores ABT-737-mediated apoptosis in human renal carcinoma cells

作者：Ou Yen Chuan; Li Jian Ri; Wang Jiaan Der; Chen Wen Ying; Kuan Yu Hsiang; Yang Ching Ping; Liao Su Lan; Lu Hsi Chi; Chen Chun Jung^*

来源：Biochemical and Biophysical Research Communications, 2018, 502(2): 187-193.

DOI：10.1016/j.bbrc.2018.05.142

• ABT-737
• Chemoprevention
• NSAID
• Renal cell carcinoma
• Resistance

Aspirin is a novel chemopreventive agent against malignancy. However, outcomes of aspirin mono therapy 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 786-0 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 mitochondria] 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.

• 出版日期2018-7-12