Transcriptomic profiling reveals akr1c1 and akr1c3 mediate cisplatin resistance in signet ring cell gastric carcinoma via autophagic cell death

Abstract

Signet ring cell gastric carcinoma (SRCGC) is a lethal malignancy that has developed drug resistance to cisplatin therapies. The aim of this study was to characterize the acquisition of the cisplatin‐resistance SRCGC cell line (KATO/DDP cells) and to understand the molecular mechanisms underlying cisplatin resistance. Transcriptomic and bioinformatic analyses were used to iden-tify the candidate gene. This was confirmed by qPCR and Western blot. Aldoketoreductase1C1 and 1C3 (AKR1C1 and AKR1C3) were the most promising molecules in KATO/DDP cells. A specific inhibitor of AKR1C1 (5PBSA) and AKR1C3 (ASP9521) was used to enhance cisplatin‐induced KATO/DPP cell death. Although cisplatin alone induced KATO/DDP apoptosis, a combination treatment of cisplatin and the AKR1C inhibitors had no influence on percent cell apoptosis. In con-junction with the autophagy inhibitor, 3MA, attenuated the effects of 5PBSA or ASP9521 to enhance cisplatin‐induced cell death. These results indicated that AKR1C1 and 1C3 regulated cisplatin‐in-duced KATO/DDP cell death via autophagy. Moreover, cisplatin in combination with AKR1C in-hibitors and N‐acetyl cysteine increased KATO/DDP cells’ viability when compared with a combination treatment of cisplatin and the inhibitors. Taken together, our results suggested that AKR1C1 and 1C3 play a crucial role in cisplatin resistance of SRCGC by regulating redox‐dependent autoph-agy.