STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

Shinji Kohsaka, Lei Wang, Kazuhiro Yachi, Roshan Mahabir, Takuhito Narita, Tamio Itoh, Mishie Tanino, Taichi Kimura, Hiroshi Nishihara, Shinya Tanaka
2012 Molecular Cancer Therapeutics  
Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA alkylating agent temozolomide (TMZ) concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to TMZ-induced DNA damage due to elevated expression of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT). Here we show that upregulation of both MGMT and STAT3 was accompanied with
more » ... tion of TMZ resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or shRNA downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of IL-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens demonstrated significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (pSTAT3) (p<0.001, r=0.58). Importantly, the levels of both MGMT and pSTAT3 were increased in the recurrence compared to the primary lesion in paired identical tumors of 12 cases. Finally, we demonstrated that STAT3 inhibitor or STAT3 knockdown potentiated TMZ efficacy in TMZ-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with TMZ for TMZ-resistant GBM patients.
doi:10.1158/1535-7163.mct-11-0801 pmid:22532597 fatcat:xdxfuz4sevbh7lbvtdeaqtcioy