Glioma Center, Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, PR China.
Oncol Rep. 2011 Nov;26(5):1173-80. doi: 10.3892/or.2011.1396. Epub 2011 Jul 19.
Activation of signal transducer and activator of transcription 3 (STAT3) is associated with poor clinical outcome of glioblastoma (GBM). However, the role of STAT3 in resistance to alkylator-based chemotherapy remains unknown. Here, we retrospectively analyzed the phosphorylated STAT3 (p-STAT3) profile of 68 GBM patients receiving alkylator therapy, identifying p-STAT3 as an independent unfavorable prognostic factor for progression-free and overall survival. Additionally, elevated p-STAT3 expression correlated with resistance to alkylator therapy. In vitro analysis revealed that U251 and U87 human glioma cells were refractory to treatment with the common alkylating agent temozolomide (TMZ), with only a modest impact on AKT and β-catenin activation in the context of high p-STAT3. Inhibition of STAT3 in these cells significantly enhanced the effect of TMZ. Inhibition of STAT3 dramatically decreased the IC50 of TMZ, increasing TMZ-induced apoptosis while up-regulating expression of Bcl-2 and down-regulating expression of Bax. Furthermore, inhibition of STAT3 increased TMZ-induced G₀-G₁ arrest and decreased Cyclin D1 expression compared to TMZ alone. Together, these results indicate that inhibition of STAT3 sensitizes glioma cells to TMZ, at least in part, by blocking the p-AKT and β-catenin pathways. These findings strongly support the hypothesis that STAT3 inhibition significantly improves the clinical efficacy of alkylating agents.
信号转导子和转录激活子 3（STAT3）的激活与胶质母细胞瘤（GBM）的不良临床结局相关。然而，STAT3 在抵抗基于烷化剂的化疗中的作用仍不清楚。在这里，我们回顾性分析了 68 名接受烷化剂治疗的 GBM 患者的磷酸化 STAT3（p-STAT3）谱，发现 p-STAT3 是无进展生存期和总生存期的独立不良预后因素。此外，升高的 p-STAT3 表达与对烷化剂治疗的耐药性相关。体外分析显示，U251 和 U87 人神经胶质瘤细胞对常见烷化剂替莫唑胺（TMZ）治疗具有抗性，在高 p-STAT3 的情况下，对 AKT 和β-连环蛋白的激活仅有适度影响。在这些细胞中抑制 STAT3 显著增强了 TMZ 的作用。抑制 STAT3 显著降低了 TMZ 的 IC50，增加了 TMZ 诱导的细胞凋亡，同时上调了 Bcl-2 的表达，下调了 Bax 的表达。此外，与 TMZ 单独治疗相比，抑制 STAT3 增加了 TMZ 诱导的 G0-G1 期阻滞并降低了 Cyclin D1 的表达。总之，这些结果表明，抑制 STAT3 通过阻断 p-AKT 和β-连环蛋白通路，至少部分地使神经胶质瘤细胞对 TMZ 敏感。这些发现有力地支持了 STAT3 抑制显著提高烷化剂临床疗效的假设。
