open access

https://hdl.handle.net/2115/52794

STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

英語

MGMT

2012-06

American Association for Cancer Research

Molecular Cancer Therapeutics

11(6)

1289-1299

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 O6-methylguanine-DNA methyltransferase (MGMT). Here we show that upregulation of both MGMT and STAT3 was accompanied with acquisition 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.

学術雑誌論文

Accepted Manuscript

1535-7163