Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death.

Nang Lae Lae Phoo,Pornngarm Dejkriengkraikul,Patompong Khaw-On,Supachai Yodkeeree

doi:10.3390/ijms222212512

Nang Lae Lae Phoo, Pornngarm Dejkriengkraikul + Show 2 more

Open Access

https://doi.org/10.3390/ijms222212512

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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 identify 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 conjunction 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-induced KATO/DDP cell death via autophagy. Moreover, cisplatin in combination with AKR1C inhibitors 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 autophagy.

Highlights

Gastric cancer is the fifth most common threat to human health worldwide according to GLOBOCAN 2018
In the last few years, there has been an overall decline in incidences of cancer; some studies have reported that there has been an abrupt increase in the occurrence of signet ring cell gastric cancer (SRCGC) in Asia, Europe, and the United States [2]
Platinum drugs appear to be effective as a first-line treatment in SRCGC patients [3], many patients still suffer from relapses and may eventually become resistant to chemotherapy

Summary

Introduction

Gastric cancer is the fifth most common threat to human health worldwide according to GLOBOCAN 2018. It has been associated with a significantly high mortality rate, making it the third leading cause of cancer-related deaths [1]. Platinum drugs (cisplatin and oxaliplatin) appear to be effective as a first-line treatment in SRCGC patients [3], many patients still suffer from relapses and may eventually become resistant to chemotherapy. This has contributed to a decrease in the 5-year survival rate. Many researchers are focusing on various mechanisms to reverse the cisplatin resistance of SRCGC

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