Okada Masashi, Sato Atsushi, Shibuya Keita, Watanabe Eriko, Seino Shizuka, Suzuki Shuhei, Seino Manabu, Narita Yoshitaka, Shibui Soichiro, Kayama Takamasa, Kitanaka Chifumi
Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
Int J Oncol. 2014 Feb;44(2):591-9. doi: 10.3892/ijo.2013.2209. Epub 2013 Dec 5.
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. O6-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.
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，但癌症干细胞对传统放化疗的高抗性仍然是一个治疗挑战。O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）在胶质母细胞瘤的癌症干细胞中经常表达，与它们对替莫唑胺（针对新诊断胶质母细胞瘤的一线化疗药物）的抗性有关。然而，关于胶质母细胞瘤癌症干细胞中MGMT表达和替莫唑胺抗性的分子调控，仍有许多未知之处。在此，我们确定JNK是控制胶质母细胞瘤癌症干细胞中MGMT表达和替莫唑胺抗性的一个新因子。我们表明，通过药理学方法或RNA干扰抑制直接来源于胶质母细胞瘤组织的类干细胞样胶质母细胞瘤细胞中的JNK，可降低其MGMT表达和替莫唑胺抗性。重要的是，通过抑制JNK使类干细胞样胶质母细胞瘤细胞对替莫唑胺敏感依赖于MGMT表达，这意味着JNK通过MGMT表达控制类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，将JNK抑制剂与替莫唑胺联合使用可能是一种合理的治疗方法，可在胶质母细胞瘤治疗中有效靶向癌症干细胞群体。
