Paul S, Bhardwaj M, Kang SC

The aim of the present study was to decipher the mechanism of glutathione?S?transferase ??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 ...

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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 TNF??induced protein 3/zinc?finger protein A20 (TNF?IP3/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 TNF?IP3/A20 as a binding partner in MDR cells. The data suggested that the expression of TNF?IP3/A20 may be dependent on GSTO1 expression in MDR cells. Targeting either GSTO1 or TNF?IP3/A20 by CRISPR/Cas9 sensitized the MDR cells to cisplatin. GSTO1 and TNF?IP3/A20 dual?KD cells were more sensitive to cisplatin compared with single?gene KD cells. These data highlight the importance of the GSTO1?TNF?IP3/A20 interaction during drug resistance.

Date: Nov. 01, 2022

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