CD147 confers temozolomide resistance of glioma cells via the regulation of β-TrCP/Nrf2 pathway

Abstract

Background: Drug resistance is one of the biggest challenges in cancer therapy. temozolomide (TMZ) represents the most important chemotherapeutic option for glioma treatment. However, the therapeutic efficacy of TMZ remains very limited due to its frequent resistance in glioma, and the underlying mechanisms were not fully addressed. Herein, we demonstrate that the elevated expression of CD147 contributes to TMZ resistance in glioma cells, potentially through the post-translational regulation of Nrf2 expression. Methods: Cell-based assays of CD147 triggered drug resistance were performed through Edu-incorporation assay, CCK8 assay, TUNEL staining assay and flow cytometric assay. Luciferase reporter assay, protein stability related assays, co-immunoprecipitation assay were used to determine CD147 induction of Nrf2 expression through β-TrCP dependent ubiquitin system. Finally, the effect of the CD147/Nrf2 signaling on glioma progression and TMZ resistance were evaluated by functional experiments and clinical samples. Results: Based on the analysis of clinical glioma tissues, CD147 is highly expressed in glioma tissues and positively associated with tumor malignancy. Suppression of CD147 expression increased the inhibitory effect of TMZ on cell survival in both U251 and T98G cells, whereas the gain of CD147 function blocked TMZ-induced ROS production and cell death. Mechanistic study indicates that CD147 inhibited GSK3β/β-TrCP-dependent Nrf2 degradation by promoting Akt activation, and subsequently increased Nrf2-mediated anti-oxidant gene expressions. Supporting the biological significance, the reciprocal relationship between CD147 and Nrf2 was observed in glioma tissues, and associated with patient outcome. Conclusions: Our data provide the first evidence that glioma resistance to TMZ is potentially due to the activation of CD147/Nrf2 axis. CD147 promotes Nrf2 stability through the suppression of GSK3β/β-TrCP dependent Nrf2 protein degradation, which results in the ablation of TMZ induced ROS production. As such, we point out that targeting CD147/Nrf2 axis may provide a new strategy for the treatment of TMZ resistant gliomas.

CD147 protein expression and Temozolomide resistance in glioma cells: an Ex vivo and In vivo study

“…Oneway analysis of variance (ANOVA) was used for continuous data. The relationship between CD147 and nuclear factor E2-related factor 2 expressions was established using linear regression and Pearson's correlation (5). For post hoc analysis, the Dunnett multiple comparisons test was used, with critical value (q) >2.549 being regarded as significant.…”

“…Numerous malignancies, including glioma, have high levels of nuclear factor E2-related factor 2, particularly in glioma stem cells (3,4). One of the transcription factors that mediate the cellular defence response is nuclear factor E2-related factor 2 (5). Genes with an anti-oxidative response element transcriptionally activated by nuclear factor E2-related factor 2, which is implicated in numerous biological processes, including tumour growth, drug resistance, and the activity of cancer stem cells (3,6,7).…”

“…A transmembrane glycoprotein, CD147 has 269 amino acids (5) and interacts with a wide variety of proteins, in-cluding integrins, matrix metallopeptidase, and monocarboxylate transporter. These proteins have been linked to the growth and spread of tumors (9).…”

“…These proteins have been linked to the growth and spread of tumors (9). However, other than cell line research, the response of CD147 to glioma cells and temozolomide resistance is not assessed elsewhere (5). The objective of l of the cell line and in vivo investigation was to show that increased CD147 expression in glioma cells leads to their resistance to temozolomide.…”

Activated TRPA1 plays a therapeutic role in TMZ resistance in glioblastoma by altering mitochondrial dynamics

“…Resistance to DNA-damaging agents, including TMZ, is usually followed by altered ROS production in mitochondria [14,15], which are the major ROS-producing organelles. ROS are mainly generated by mitochondria as electrons leak from electron transport chains, which leads to partial oxygen reduction and superoxide formation [16]. Mitochondria are subcellular organelles with double membranes.…”