Abstract

Temozolomide resistance is a major cause of recurrence and poor prognosis in neuroglioma. Recently, growing evidence has suggested that mitophagy is involved in drug resistance in various tumor types. However, the role and molecular mechanisms of mitophagy in temozolomide resistance in glioma remain unclear. In this study, mitophagy levels in temozolomide-resistant and -sensitive cell lines were evaluated. The mechanisms underlying the regulation of mitophagy were explored through RNA sequencing, and the roles of differentially expressed genes in mitophagy and temozolomide resistance were investigated. We found that mitophagy promotes temozolomide resistance in glioma. Specifically, small ubiquitin-like modifier specific protease 6 (SENP6) promoted temozolomide resistance in glioma by inducing mitophagy. Protein-protein interactions between SENP6 and the mitophagy executive protein PTEN-induced kinase 1 (PINK1) resulted in a reduction in small ubiquitin-like modifier 2 (SUMO2)ylation of PINK1, thereby enhancing mitophagy. Our study demonstrates that by inducing mitophagy, the interaction of SENP6 with PINK1 promotes temozolomide resistance in glioblastoma. Therefore, targeting SENP6 or directly regulating mitophagy could be a potential and novel therapeutic target for reversing temozolomide resistance in glioma.

中文翻译：

---

SENP6 与 PINK1 的相互作用通过诱导线粒体自噬促进神经胶质瘤细胞中的替莫唑胺耐药

摘要

替莫唑胺耐药是神经胶质瘤复发和预后不良的主要原因。最近，越来越多的证据表明线粒体自噬与多种肿瘤类型的耐药性有关。然而，线粒体自噬在神经胶质瘤替莫唑胺耐药中的作用和分子机制仍不清楚。在这项研究中，评估了替莫唑胺耐药和敏感细胞系的线粒体自噬水平。通过RNA测序探讨线粒体自噬调控机制，并研究差异表达基因在线粒体自噬和替莫唑胺耐药中的作用。我们发现线粒体自噬促进神经胶质瘤对替莫唑胺的耐药性。具体来说，小泛素样修饰特异性蛋白酶 6 (SENP6) 通过诱导线粒体自噬促进神经胶质瘤中的替莫唑胺耐药性。SENP6 和线粒体自噬执行蛋白 PTEN 诱导激酶 1 (PINK1) 之间的蛋白质-蛋白质相互作用导致 PINK1 的小泛素样修饰剂 2 (SUMO2) 化减少，从而增强线粒体自噬。我们的研究表明，通过诱导线粒体自噬，SENP6 与 PINK1 的相互作用促进胶质母细胞瘤中的替莫唑胺耐药。因此，靶向 SENP6 或直接调节线粒体自噬可能是逆转神经胶质瘤替莫唑胺耐药的潜在新治疗靶点。