期刊
AMERICAN JOURNAL OF CHINESE MEDICINE
卷 47, 期 3, 页码 657-674出版社
WORLD SCIENTIFIC PUBL CO PTE LTD
DOI: 10.1142/S0192415X19500344
关键词
Connexin 43; Glioma; Curcumin; Temozolomide; Chemoresistance
资金
- Ministry of Science and Technology [NSC 102-2320-B-039-051-MY3, MOST 105-2320-B-468-004-MY3]
- China Medical University [CMU 107-ASIA-16]
- Taichung Tzu Chi Hospital [TTCRD105-05]
Glioblastoma (GBM) is the most commonly occurring tumor in the cerebral hemispheres. Currently, temozolomide (TMZ), an alkylating agent that induces DNA strand breaks, is considered the frontline chemotherapeutic agent for GBM. Despite its frontline status, GBM patients commonly exhibit resistance to TMZ treatment. We have recently established and characterized TMZ-resistant human glioma cells. The aim of this study is to investigate whether curcumin modulates cell apoptosis through the alternation of the connexin 43 (Cx43) protein level in TMZ-resistant GBM. Overexpression of Cx43, but not ATP-binding cassette transporters (ABC transporters), was observed (approximately 2.2-fold) in TMZ-resistant GBM cells compared to the Cx43 levels in parental GBM cells. Furthermore, at a concentration of 10 mu M, curcumin significantly reduced Cx43 protein expression by about 40%. In addition, curcumin did not affect the expression of other connexins like Cx26 or epithelial-to-mesenchymal transition (EMT) proteins such as beta-catenin or alpha E-catenin. Curcumin treatment led to an increase in TMZ-induced cell apoptosis from 4% to 8%. Importantly, it did not affect the mRNA expression level of Cx43. Concomitant treatment with the translation inhibitor cycloheximide (CHX) exerted additional effects on Cx43 degradation. Treatment with the autophagy inhibitor 3-MA (methyladenine) did not affect the curcumin-induced Cx43 degradation. Interestingly, treatment with the proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) significantly negated the curcumin-induced Cx43 degradation, which suggests that curcum-ininduced Cx43 degradation occurs through the ubiquitin-proteasome pathway.
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