State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
Department of Neurosurgery, Wuxi Second Hospital Affiliated Nanjing Medical University, Wuxi, Jiangsu, 214002, China.
Cell Death Dis. 2018 Feb 7;9(2):190. doi: 10.1038/s41419-017-0251-9.
Resistance to temozolomide (TMZ) is a major clinical challenge in glioma treatment, but the mechanisms of TMZ resistance are poorly understood. Here, we provided evidence that ROCK2 acted redundantly to maintain resistance of TMZ in TMZ-resistant gliomas, and as a ROCK2 phosphorylation inhibitor, fasudil significantly suppressed proliferation of TMZ-resistant gliomas in vivo and vitro via enhancing the chemosensitivity of TMZ. Additionally, the membrane translocation of ABCG2 was decreased with fasudil by ROCK2/moesin pathway. We also showed that fasudil suppressed the expression of ABCG2 via ROCK2/moesin/β-catenin pathway. Our results reveal an indispensable role for ROCK2 and provide strong evidence for the therapeutic use of fasudil in the clinical setting for TMZ-resistant gliomas.
替莫唑胺（TMZ）耐药是胶质瘤治疗中的主要临床挑战，但 TMZ 耐药的机制仍不清楚。在这里，我们提供的证据表明，ROCK2 通过维持 TMZ 耐药性在 TMZ 耐药性胶质瘤中发挥冗余作用，并且作为 ROCK2 磷酸化抑制剂，法舒地尔通过增强 TMZ 的化疗敏感性，显著抑制体内和体外 TMZ 耐药性胶质瘤的增殖。此外，通过 ROCK2/黏着斑蛋白途径，fasudil 降低了 ABCG2 的膜易位。我们还表明，fasudil 通过 ROCK2/黏着斑蛋白/β-连环蛋白途径抑制 ABCG2 的表达。我们的结果揭示了 ROCK2 的不可或缺的作用，并为 fasudil 在 TMZ 耐药性胶质瘤的临床治疗中的应用提供了有力的证据。
