Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Department of Pharmacy, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Eur J Pharmacol. 2019 Nov 15;863:172665. doi: 10.1016/j.ejphar.2019.172665. Epub 2019 Sep 19.
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.
神经胶质瘤是最致命的恶性肿瘤之一，其驱动神经胶质瘤发生的分子调控因子尚未完全阐明。虽然替莫唑胺（TMZ）已被应用于恶性神经胶质瘤作为一种经典的化疗药物，但由于经常对 TMZ 产生耐药性，神经胶质瘤的治疗仍然受到限制。因此，开发能够使神经胶质瘤细胞对 TMZ 敏感的有前途的策略是至关重要的。在这里，我们发现二氢叶酸还原酶（DHFR）和胸苷酸合成酶（TYMS）的表达在人神经胶质瘤组织和细胞系中均上调，它们在叶酸代谢和几种类型的肿瘤中发挥着重要作用，DHFR/TYMS 的过表达促进了神经胶质瘤细胞的增殖。值得注意的是，培美曲塞抑制 DHFR/TYMS 在细胞系和 U251 异种移植中与 TMZ 表现出协同抗神经胶质瘤活性，这表明对神经胶质瘤具有潜在的联合化疗作用。在机制上，DHFR/TYMS 与 TMZ 的协同抑制作用是由于 AMPK 的激活，随后抑制了 mTOR 信号通路。总之，这些发现确定了 DHFR/TYMS 在 AMPK-mTOR 信号通路介导的神经胶质瘤生长和 TMZ 敏感性中的一个未被描述的作用，并为提高 TMZ 在神经胶质瘤中的抗肿瘤活性提供了一种有前景的方法。
