JNK contributes to temozolomide resistance of stem-like glioblastoma cells via regulation of MGMT expression
JNK contributes to temozolomide resistance of stem-like glioblastoma cells via regulation of MGMT expression
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DOI：
10.3892/ijo.2013.2209
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发表时间：
2014-02-01
影响因子：
5.2
通讯作者：
Kitanaka, Chifumi
中科院分区：
文献类型：
--
作者：
Okada, Masashi;Sato, Atsushi;Kitanaka, Chifumi
虽然消除癌症干细胞群体越来越被认为是成功治疗癌症的关键，但癌症干细胞对常规放化疗的高抗性仍然是治疗挑战。O-6-甲基鸟嘌呤DNA甲基转移酶（MGMT）在胶质母细胞瘤的肿瘤干细胞中频繁表达，与肿瘤干细胞对替莫唑胺（新诊断胶质母细胞瘤的一线化疗药物）的耐药性有关。然而，关于胶质母细胞瘤干细胞MGMT表达和替莫唑胺耐药的分子调控仍有许多未知之处。在这里，我们确定JNK作为一个新的球员在控制MGMT表达和替莫唑胺耐药性的胶质母细胞瘤癌症干细胞。我们发现，JNK的抑制，无论是直接从胶质母细胞瘤组织衍生的干细胞样胶质母细胞瘤细胞，RNA干扰，减少他们的MGMT表达和替莫唑胺耐药。重要的是，通过JNK抑制对替莫唑胺的干细胞样胶质母细胞瘤细胞的敏化依赖于MGMT表达，这意味着JNK通过MGMT表达控制干细胞样胶质母细胞瘤细胞的替莫唑胺抗性。我们的研究结果表明，同时使用JNK抑制剂与替莫唑胺可能是一种合理的治疗方法，有效地靶向治疗胶质母细胞瘤的癌症干细胞群体。
While elimination of the cancer stem cell population is increasingly recognized as a key to successful treatment of cancer, the high resistance of cancer stem cells to conventional chemoradiotherapy remains a therapeutic challenge. O-6-methylguanine DNA methyltransferase (MGMT), which is frequently expressed in cancer stem cells of glioblastoma, has been implicated in their resistance to temozolomide, the first-line chemotherapeutic agent against newly diagnosed glioblastoma. However, much remains unknown about the molecular regulation that underlies MGMT expression and temozolomide resistance of glioblastoma cancer stem cells. Here, we identified JNK as a novel player in the control of MGMT expression and temozolomide resistance of glioblastoma cancer stem cells. We showed that inhibition of JNK, either pharmacologically or by RNA interference, in stem-like glioblastoma cells derived directly from glioblastoma tissues reduces their MGMT expression and temozolomide resistance. Importantly, sensitization of stem-like glioblastoma cells to temozolomide by JNK inhibition was dependent on MGMT expression, implying that JNK controls temozolomide resistance of stem-like glioblastoma cells through MGMT expression. Our findings suggest that concurrent use of JNK inhibitors with temozolomide may be a rational therapeutic approach to effectively target the cancer stem cell population in the treatment of glioblastoma.