STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

Apr 26, 2012Molecular cancer therapeutics

Blocking STAT3 may reduce drug resistance in brain cancer by lowering MGMT levels

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Abstract

Significant positive correlation (P < 0.001, r = 0.58) exists between expression levels of MGMT and phosphorylated STAT3 in malignant glioma specimens.

Upregulation of MGMT and STAT3 is associated with temozolomide resistance in the GBM cell line U87.
Inactivation of STAT3 through inhibitors or short hairpin RNA leads to downregulation of MGMT in GBM cell lines.
Interleukin-6 treatment does not result in MGMT upregulation despite being a strong activator of STAT3.
Forced expression of MGMT can be reduced by a STAT3 inhibitor, which is partially reversed by the proteasome inhibitor MG132.
Increased levels of MGMT and phosphorylated STAT3 are noted in recurrent tumors compared to primary lesions in paired cases.
STAT3 inhibition enhances the efficacy of temozolomide in temozolomide-resistant GBM cell lines.

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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 concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide-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 acquisition of temozolomide resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or short hairpin RNA (shRNA) downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of interleukin (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 showed significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (p-STAT3; P < 0.001, r = 0.58). Importantly, the levels of both MGMT and p-STAT3 were increased in the recurrence compared with the primary lesion in paired identical tumors of 12 cases. Finally, we showed that STAT3 inhibitor or STAT3 knockdown potentiated temozolomide efficacy in temozolomide-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with temozolomide for patients with temozolomide-resistant GBM.

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STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

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