Curcumin Promotes Connexin 43 Degradation and Temozolomide-Induced Apoptosis in Glioblastoma Cells

Abstract

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[Formula: see text][Formula: see text]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 [Formula: see text]-catenin or [Formula: see text]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 curcumin-induced Cx43 degradation occurs through the ubiquitin-proteasome pathway.

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“…Researchers already confirmed that the connexin gene family played a complicated role in tumorigenesis and progression 21 . Recently researcher found that GJA1 was associated in glioblastoma cancer cells apoptosis and promote the progression and invasion in breast cancer cells 22,23 . Few research about GJA1 was conducted in GCa, one of them suggested that overexpression of GJA1 leads to decreased ability of colony forming and invasive ability in BGC‐823 cells, 24 which was consistent with our research results.…”

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“…In glioblastoma (GBM), overexpression of GJA1 was observed in temozolomide-resistant GBM cells. 34 In ovarian cancer, TATA-box binding protein (TBP) contributes to regulation of dedifferentiation states that promote metastasis and chemoresistance. 35 In breast cancer, miR-141 mediated docetaxel resistance through direct interactions with EIF-4E.…”

Autophagy as a Potential Therapy for Malignant Glioma

“…Huang et al suggested TMZ-resistant GBM cells could be sensitized to the treatment by co-administering curcumin plus TMZ, downregulating Cx43. Curcumin sensitized TMZ-resistant cells, decreasing Cx43 expression by 40% via the ubiquitin-proteasome pathway, inducing high apoptosis rates [233].…”