8-Azaguanine-induced autophagy contributes to its chemoresistance in hepatic cancer cells
10.16438/j.0513-4870.2020-1511
- VernacularTitle:8-氮鸟嘌呤通过Akt/mTORC1/ULK1诱导细胞自噬增强其在肝癌细胞中的耐药性
- Author:
Jun-ting XU
;
Dian-long LI
;
Xu WANG
;
Jie-ru LIN
;
Yan-fei HAO
;
Xin-peng ZHANG
;
Ai-po DIAO
;
Zhen-xing LIU
- Publication Type:Research Article
- Keywords:
8-azaguanine;
chemoresistance;
autophagy;
Akt/mTORC1;
apoptosis
- From:
Acta Pharmaceutica Sinica
2021;56(3):799-807
- CountryChina
- Language:Chinese
-
Abstract:
Autophagy, an evolutionarily conserved process by which components of the cell are degraded in lysosomes, may facilitate survival of cancer cells under stress conditions. 8-Azaguanine (8-AG), an inhibitor of purine nucleotide biosynthesis, shows antineoplastic activity in multiple tumor cells. However, chemoresistance has restricted its development as an anticancer agent, and the mechanism of 8-AG resistance is not fully understood. We report here that 8-AG induces a protective autophagy to eliminate its cytotoxicity, and inhibition of autophagy increases cellular sensitivity of cancer cells to 8-AG treatment. Using HepG2 or SMMC-7721 hepatic cancer cell lines, we found that 8-AG inhibited cell viability and induced intrinsic apoptosis, accompanied by the up-regulation of the pro-apoptotic protein BimS, one of Bim (also known as BCL-2-like protein 11, BCL2L11) isoforms. Furthermore, 8-AG treatment enhanced the autophagy flux by promoting the dephosphorylation and activation of Unc-51-like autophagy activating kinase 1 (ULK1) via Akt/mTORC1 (mammalian target of rapamycin complex 1) signaling inhibition. Depletion of autophagy-related gene 7 (ATG7) markedly enhanced the level of BimS, and promoted cell death in response to 8-AG. 8-AG in combination with autophagy inhibitor chloroquine (CQ) or bafilomycin A1 (Baf A1) promoted the 8-AG-induced apoptosis in hepatic cancer cells. Altogether, these findings suggest that autophagy promotes chemoresistance of cancer cells for 8-AG, and blocking autophagy increases cellular sensitivity of cancer cells to 8-AG treatment.
