Lee Eun-Sang, Ko Kyung-Kon, Joe Young Ae, Kang Seok-Gu, Hong Yong-Kil
Cancer Research Institute, The Catholic University of Korea, Seoul 137-701, Korea.
Oncol Lett. 2011 Jan;2(1):115-121. doi: 10.3892/ol.2010.210. Epub 2010 Nov 23.
The alkylating agent temozolomide (TMZ) is an effective drug used for the treatment of malignant gliomas. However, tumor relapse combined with the development of drug resistance remains a significant problem. To clarify the mechanism of the resistance of glioma cells to TMZ chemotherapy, TMZ-resistant glioma cell lines (TR cells) were generated using U373 and U251 human glioma cells, and TMZ-resistance was confirmed via viability and apoptosis assays. The TMZ-resistance of TR cells was not associated with the TMZ-resistance molecule O(6)-methylguanine-DNA-methyltransferase. Notably, the expression level of signal transducers and activators of transcription 3 (STAT3) and serine 727-phosphorylated STAT3 (pSTAT3-Ser727) was highly increased in TR cells, while that of 705-phosphorylated STAT3 (pSTAT3-Tyr705) was decreased. The inhibition of STAT3 expression by small interfering RNA enhanced TR cell TMZ sensitivity. These results suggest that STAT3 contributes to TMZ-resistance in gliomas and is a potential target for the reversal of TMZ-resistance in patients with a recurrent glioma.
烷化剂替莫唑胺（TMZ）是一种用于治疗恶性胶质瘤的有效药物。然而，肿瘤复发以及耐药性的产生仍然是一个重大问题。为了阐明胶质瘤细胞对TMZ化疗耐药的机制，利用U373和U251人胶质瘤细胞构建了TMZ耐药的胶质瘤细胞系（TR细胞），并通过活力和凋亡检测证实了其耐药性。TR细胞的TMZ耐药性与TMZ耐药分子O(6)-甲基鸟嘌呤-DNA甲基转移酶无关。值得注意的是，转录信号转导子和激活子3（STAT3）以及丝氨酸727磷酸化的STAT3（pSTAT3-Ser727）在TR细胞中的表达水平显著升高，而酪氨酸705磷酸化的STAT3（pSTAT3-Tyr705）的表达水平则降低。小干扰RNA抑制STAT3表达可增强TR细胞对TMZ的敏感性。这些结果表明，STAT3在胶质瘤对TMZ的耐药中起作用，并且是复发性胶质瘤患者逆转TMZ耐药的潜在靶点。
