期刊
DRUG RESISTANCE UPDATES
卷 67, 期 -, 页码 -出版社
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.drup.2023.100930
关键词
Colorectal cancer; Thiol oxidative stress; TGM2; 5-Fluorouracil; Apoptosis; S -glutathionylation
5-Fluorouracil (5-Fu) is a first-line drug for colorectal cancer (CRC) therapy. However, the development of 5-Fu resistance limits its effectiveness and leads to poor prognosis. Transglutaminase 2 (TGM2) is associated with chemoresistance in CRC and is regulated by thiol oxidative stress. Upregulation of thiol oxidative stress reverses 5-Fu resistance through downregulation of TGM2 and enhances apoptosis. TGM2 may serve as a potential therapeutic target for treating 5-Fu-resistant CRC.
5-Fluorouracil (5-Fu) is a first-line drug for colorectal cancer (CRC) therapy. However, the development of 5-Fu resistance limits its chemotherapeutic effectiveness and often leads to poor prognoses of CRC. Transglutaminase 2 (TGM2), a member of the transglutaminase family, is considered to be associated with chemoresistance through apoptotic prevention in various cancers including CRC. TGM2 was found to be overexpressed in two 5-Fu-resistant CRC cell lines and down-regulated by increased thiol oxidative stress induced by inhibition of glutathione reductase (GR). The present study aimed to explore the role of TGM2 in 5-Fu-resistant CRC and the mechanism of action by which the elevated thiol oxidative stress down-regulates TGM2 protein level. The results revealed that 5-Fu-resistance induced by overexpression of TGM2 in CRC cells was reversed through up-regulation of thiol oxidative stress. Knockdown of TGM2 increased the chemosensitivity of CRC cells to 5-Fu. Thiol oxidative stress potentially enhanced the therapeutic effect of 5-Fu in the resistant CRC cells by promo-tion of 5-Fu-induced apoptosis through down-regulation of TGM2. The elevated thiol oxidative stress increased the S-glutathionylation of TGM2 and led to proteasomal degradation of TGM2. Furthermore, Cys193 was identified as the S-glutathionylation site in TGM2, and its mutation resulted in thiol oxidative stress-mediated CRC cell apoptotic resistance. TGM2-induced EMT was also suppressed by the elevated thiol oxidative stress. A xenograft tumor model confirmed the effect of thiol oxidative stress in the reversal of 5-Fu resistance in CRC cells in vivo. TGM2 protein expression level was found to be significantly higher in human CRC specimens than in non-cancerous colorectal tissues. Taken together, the present data suggest an important role of TGM2 in 5-Fu resistance in CRC cells. Up-regulation of thiol oxidative stress could be a potential therapeutic approach for treating 5-Fu-resistant CRC and TGM2 may serve as a potential therapeutic target of thiol oxidative stress.
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