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

Journal Article · Sun Jul 15 04:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.05.142· OSTI ID:23105745

Ou, Yen-Chuan ^[1]; Li, Jian-Ri ^[2]; Wang, Jiaan-Der ^[3]; Chen, Wen-Ying ^[4]; Kuan, Yu-Hsiang ^[5]; Yang, Ching-Ping; Liao, Su-Lan ^[6]; Lu, Hsi-Chi ^[7]; Chen, Chun-Jung ^[6]

---

1. Department of Urology, Tungs' Taichung MetroHarbor Hospital, Taichung (China)
2. Division of Urology, Taichung Veterans General Hospital, Taichung (China)
3. Department of Pediatrics & Child Health Care, Taichung Veterans General Hospital, Taichung (China)
4. Department of Veterinary Medicine, National Chung Hsing University, Taichung (China)
5. Department of Pharmacology, Chung Shan Medical University, Taichung (China)
6. Department of Medical Research, Taichung Veterans General Hospital, Taichung (China)
7. Food Science Department and Graduate Institute, Tunghai University, Taichung (China)

Highlights: • Aspirin and ABT-737 combination induced 786-O cell apoptosis. • Aspirin and ABT-737 combination-induced apoptosis involving Mcl-1 downregulation. • Aspirin and ABT-737 combination activated PP2A. • Okadaic acid attenuated aspirin and ABT-737 combination-induced apoptosis. 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.

• OSTI ID: 23105745
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 502; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACETYLSALICYLIC ACID
CARCINOMAS
MITOCHONDRIA
PHOSPHATASES