Arefnezhd Reza, Chahardehi Amir Modarresi, Asadi Amirmasoud, Shadravan Mahammad Mehdi, Shariati Abbas, Rezaee Aryan, Radmanesh Mehrsa, Nazarian Mohammadreza, Helfi Maryam, Soleimani Meigoli Mohammad Saeed, Motedayyen Hossein, Rezaei-Tazangi Fatemeh, Tavakoli Marziye Ranjbar
Coenzyme R Research Institute, Tehran, Iran.
Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.
Brain Tumor Pathol. 2025 Apr 21. doi: 10.1007/s10014-025-00501-7.
Radiotherapy remains a cornerstone of brain tumor treatment; however, its effectiveness is frequently undermined by the development of radioresistance. This review highlights the pivotal role of molecular chaperones in promoting radioresistance and explores the potential to increase radioresistance in brain cancers, particularly glioblastoma (GBM). Among chaperones, heat shock proteins (HSPs), such as HSP70 and HSP90, have been identified as key contributors to radioresistance, acting through mechanisms that include the maintenance of protein homeostasis, enhancement of DNA repair processes, and protection of cancer stem cells. Specifically, HSP70 and HSP90 are crucial in stabilizing oncogenic proteins and preventing apoptosis, thus enabling tumor survival during radiotherapy. Also, HSP27 and GRP78 are involved in the radioresistance of brain tumors mainly by suppressing cell death and enhancing tumor stem cell propagation. Emerging evidence also suggests that targeting these chaperones, in combination with radiotherapy, can enhance tumor radiosensitivity, offering promising therapeutic strategies. Recent studies have revealed novel aspects of chaperone-mediated autophagy and interaction with non-coding RNAs, providing deeper insights into the molecular mechanisms underlying radioresistance. This review also addresses the potential of combining chaperone-targeted therapies, such as HSP90 inhibitors, with radiotherapy to overcome resistance. Ultimately, understanding these mechanisms may pave the way for innovative clinical applications and personalized therapeutic approaches in brain tumor treatment.
放射治疗仍然是脑肿瘤治疗的基石；然而，其有效性常常因放射抗性的产生而受到削弱。本综述强调了分子伴侣在促进放射抗性方面的关键作用，并探讨了提高脑癌尤其是胶质母细胞瘤（GBM）放射抗性的潜力。在伴侣蛋白中，热休克蛋白（HSPs），如HSP70和HSP90，已被确定为放射抗性的关键促成因素，其作用机制包括维持蛋白质稳态、增强DNA修复过程以及保护癌症干细胞。具体而言，HSP70和HSP90在稳定致癌蛋白和防止细胞凋亡方面至关重要，从而使肿瘤在放射治疗期间得以存活。此外，HSP27和GRP78主要通过抑制细胞死亡和增强肿瘤干细胞增殖参与脑肿瘤的放射抗性。新出现的证据还表明，靶向这些伴侣蛋白并结合放射治疗可增强肿瘤的放射敏感性，提供了有前景的治疗策略。最近的研究揭示了伴侣蛋白介导的自噬以及与非编码RNA相互作用的新方面，为放射抗性的分子机制提供了更深入的见解。本综述还探讨了将靶向伴侣蛋白的疗法，如HSP90抑制剂，与放射治疗相结合以克服抗性的潜力。最终，了解这些机制可能为脑肿瘤治疗中的创新临床应用和个性化治疗方法铺平道路。
