DHFR/TYMS are positive regulators of glioma cell growth and modulate chemo-sensitivity to temozolomide
DHFR/TYMS are positive regulators of glioma cell growth and modulate chemo-sensitivity to temozolomide
复制标题
DHFR/TYMS 是神经胶质瘤细胞生长的正调节剂并调节对替莫唑胺的化疗敏感性
DOI：
10.1016/j.ejphar.2019.172665
复制
发表时间：
2019
影响因子：
5
通讯作者：
Weng Qinjie
中科院分区：
文献类型：
--
作者：
Zhao Mengting;Tan Biqin;Dai Xiaoyang;Shao Yanfei;He Qiaojun;Yang Bo;Wang Jincheng;Weng Qinjie
胶质瘤是最致命的恶性肿瘤之一，而驱动胶质瘤发生的分子调控因子尚不完全清楚。尽管替莫唑胺（TMZ）已被用作恶性胶质瘤的典型化疗药物，但由于其耐药性的频繁发生，胶质瘤的治疗仍然受到限制。因此，有前途的策略，敏感神经胶质瘤细胞替莫唑胺是压倒性的发展。我们发现在叶酸代谢和多种肿瘤中起重要作用的二氢叶酸还原酶（DHFR）和胸苷酸合成酶（TYMS）在人脑胶质瘤组织和细胞系中表达上调，并且过表达DHFR/TYMS促进胶质瘤细胞的增殖。值得注意的是，培美曲塞对DHFR/TYMS的抑制作用与TMZ在细胞系和U251异种移植物中均表现出协同抗胶质瘤活性，这表明潜在的胶质瘤联合化疗。从机制上讲，DHFR/TYMS与TMZ抑制的协同效应是由于激活AMPK并随后抑制mTOR信号通路。综上所述，这些发现证实了DHFR/TYMS在胶质瘤生长和AMPK-mTOR信号通路介导的TMZ敏感性中的未表征作用，并为提高TMZ在胶质瘤中的抗肿瘤活性提供了前瞻性方法。
Glioma is one of the most lethal malignancies and molecular regulators driving gliomagenesis are incompletely understood. Although temozolomide (TMZ) has been applied for malignant gliomas as a canonical chemotherapy, the treatment of glioma still remains limited due to frequently developed resistance to TMZ. Therefore, promising strategies that sensitize glioma cells to temozolomide are overwhelming to develop. Here we found that the expression of dihydrofolate reductase (DHFR) and thymidylate synthetase (TYMS), which played an essential role in folate metabolism and several types of tumors, were up-regulated in both human glioma tissues and cell lines, and overexpression of DHFR/TYMS promoted the proliferation of glioma cells. Notably, inhibition of DHFR/TYMS by pemetrexed exhibited synergistic anti-glioma activity with TMZ in both cell lines and U251 xenografts, which suggested potential combined chemotherapy for glioma. Mechanistically, the synergistic effect of inhibition of DHFR/TYMS with TMZ was due to activated AMPK and subsequently suppressed mTOR signaling pathway. Taken together, these findings identify an uncharacterized role of DHFR/TYMS in glioma growth and TMZ sensitivity mediated by AMPK-mTOR signal pathway, and provide a prospective approach for improving the anti-tumor activity of TMZ in glioma.