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

Abstract

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.

• Authors: 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
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 502 Issue 2 Pg. 187-193 (07 12 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 29792865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• ABT-737
• Anticarcinogenic Agents
• Biphenyl Compounds
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Nitrophenols
• Piperazines
• RNA, Small Interfering
• Sulfonamides
• Proto-Oncogene Proteins c-akt
• Protein Phosphatase 2
• Aspirin

Topics

• Anticarcinogenic Agents (administration & dosage)
• Apoptosis (drug effects)
• Aspirin (administration & dosage)
• Biphenyl Compounds (administration & dosage)
• Carcinoma, Renal Cell (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Humans
• Kidney Neoplasms (drug therapy, metabolism, pathology)
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, genetics, metabolism)
• Nitrophenols (administration & dosage)
• Piperazines (administration & dosage)
• Protein Phosphatase 2 (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (genetics)
• Sulfonamides (administration & dosage)