GSTO1 confers drug resistance in HCT‑116 colon cancer cells through an interaction with TNFαIP3/A20

Abstract

The aim of the present study was to decipher the mechanism of glutathione-S-transferase Ω-1 (GSTO1)-induced drug resistance in colon cancer cells. Cisplatin is used widely as a therapeutic drug in cancer, but colon cancer is the most susceptible to acquired drug resistance. Autophagy is recognized as one of the contributors to drug resistance in cancers. Phase II detoxifying enzymes, such as GSTO1, serve important roles in autophagy-apoptosis cross talk. The present study revealed a novel interaction between GSTO1 and TNFα-induced protein 3/zinc-finger protein A20 (TNFαIP3/A20) as a prime target for cisplatin sensitization in drug-resistant cells. GSTO1 and ATP-binding cassette subfamily B member 1 (ABCB1) were both expressed at higher levels in multidrug-resistant (MDR) HCT-116 cells compared with the wild-type (WT) HCT-116 cells, suggesting they may serve vital roles in multidrug resistance. MDR cells showed autophagy induction, which is dependent on calcium signaling-dependent endoplasmic stress. In WT cells, the mitochondria-dependent pathway leads to apoptosis, which was not observed in MDR cells. The MDR conditions were mimicked by transfecting WT cells with the GSTO1-activation CRISPR plasmid, which induced autophagy. Similarly, MDR cells with GSTO1-knockdown (KD) CRISPR/ Cas9 transfection showed reduced autophagy with increased apoptosis. These data revealed a potentially important role of GSTO1 in drug resistance. A GSTO1 pull-down assay detected TNFαIP3/A20 as a binding partner in MDR cells. The data suggested that the expression of TNFαIP3/A20 may be dependent on GSTO1 expression in MDR cells. Targeting either GSTO1 or TNFαIP3/A20 by CRISPR/Cas9 sensitized the MDR cells to cisplatin. GSTO1 and TNFαIP3/A20 dual-KD cells were more sensitive to cisplatin compared with single-gene KD cells. These data highlight the importance of the GSTO1-TNFαIP3/A20 interaction during drug resistance.

The Role of Glutathione Transferase Omega-Class Variant Alleles in Individual Susceptibility to Ovarian Cancer

“…So far, an association between the GSTO1*C419A polymorphism (rs4925) and susceptibility to various cancers, including acute lymphoblastic leukemia, hepatocellular, breast, bile duct, non-small cell lung, colon, and testicular cancer has been confirmed [33,40]. On the other hand, the GSTO2*A424G polymorphism (rs156697) has been shown to be associated with ovarian, breast, urinary bladder, and renal cell cancers, which is in agreement with the results of our study [33,37,[41][42][43]. The rationale for these associations might be both in the regulatory and antioxidant roles of omega-class glutathione transferases.…”

Glutathione S‐transferase omega class 1 (GSTO1)‐associated large extracellular vesicles are involved in tumor‐associated macrophage‐mediated cisplatin resistance in bladder cancer

“…2E). In addition, previous studies have reported the involvement of GSTO1 in cisplatin resistance in colon cancer [16]. However, the role of GSTO1 in drug resistance, specifically in bladder cancer, has never been investigated.…”

“…Upregulation of GSTO1 expression is reported for diverse cancers, including esophageal squamous cell carcinoma [11], colorectal cancer [12], non-small-cell lung cancer [13], and bladder cancer [14], and is associated with metastatic features and advanced cancer stages. In addition, GSTO1 is suggested to be involved in chemoresistance in ovarian [15], colon [16], and cervical [17] cancers. The GSTO1 inhibitor sensitizes melanoma to cisplatin treatment [18].…”

Application of CRISPR-Cas9 gene editing technology in basic research, diagnosis and treatment of colon cancer

“…The interaction between GSTO1 and TNFαIP3/A20 promotes the generation of drug resistance. Studies have found that double gene knockout of GSTO1 and TNFαIP3/A20 using the CRISPR/Cas9 system is more sensitive to chemotherapy drugs than single gene knockout, and the apoptosis of cancer cells increases, which reveals that GSTO1 can enhance the drug resistance of cancer cells ( 49 ).…”