Research Paper Volume 13, Issue 5 pp 7300—7313
Maf1 suppression of ATF5-dependent mitochondrial unfolded protein response contributes to rapamycin-induced radio-sensitivity in lung cancer cell line A549
- 1 Department of General Surgery, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China
- 2 Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Changsha 410008, Hunan, China
- 3 Department of Oncology, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China
- 4 Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
Received: October 22, 2020 Accepted: December 23, 2020 Published: February 26, 2021https://doi.org/10.18632/aging.202584
How to Cite
Copyright: © 2021 Lai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
mTOR is well known to promote tumor growth but its roles in enhancing chemotherapy and radiotherapy have not been well studied. mTOR inhibition by rapamycin can sensitize cancer cells to radiotherapy. Here we show that Maf1 is required for rapamycin to increase radio-sensitivity in A549 lung cancer cells. In response to ionizing radiation (IR), Maf1 is inhibited by Akt-dependent re-phosphorylation, which activates mitochondrial unfolded protein response (UPRmt) through ATF5. Rapamycin suppresses IR-induced Maf1 re-phosphorylation and UPRmt activation in A549 cells, resulting in increased sensitivity to IR-mediated cytotoxicity. Consistently, Maf1 knockdown activates ATF5-transcription of mtHSP70 and HSP60, enhances mitochondrial membrane potential, reduces intracellular ROS levels and dampens rapamycin’s effect on increasing IR-mediated cytotoxicity. In addition, Maf1 overexpression suppresses ethidium bromide-induced UPRmt and enhances IR-mediated cytotoxicity. Supporting our cell-based studies, elevated expression of UPRmt makers (mtHSP70 and HSP60) are associated with poor prognosis in patients with lung adenocarcinoma (LAUD). Together, our study reveals a novel role of Maf1-UPRmt axis in mediating rapamycin’s enhancing effect on IR sensitivity in A549 lung cancer cells.