Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
Cell Death Dis. 2017 May 18;8(5):e2807. doi: 10.1038/cddis.2017.217.
Cancer is the second leading cause of death worldwide. Current treatment strategies based on multi-agent chemotherapy and/or radiation regimens have improved overall survival in some cases. However, resistance to apoptosis often develops in cancer cells, and its occurrence is thought to contribute to treatment failure. Non-apoptotic cell death mechanisms have become of great interest, therefore, in hopes that they would bypass tumor cell resistance. Glioblastoma multiforme (GBM), a grade IV astrocytic tumor is the most frequent brain tumor in adults, and has a high rate of mortality. We report that NIM811, a small molecule cyclophilin-binding inhibitor, induces catastrophic vacuolization and cell death in GBM cells. These unique features are distinct from many known cell death pathways, and are associated with an incompletely defined cell death mechanism known as paraptosis. We found that NIM811-induced paraptosis is due to unresolved ER stress. The abnormal upregulation of protein translation was responsible for the build-up of misfolded or unfolded proteins in ER, whereas pro-survival autophagy and UPR signals were shutdown during prolonged treatment with NIM811. Although cycloheximide has been claimed to suppress paraptosis, instead we find that it only temporarily delayed vacuole formation, but actually enhanced paraptotic cell death in the long term. On the other hand, mTOR inhibitors rescued cells from NIM811-induced paraptosis by sustaining autophagy and the UPR, while specifically restraining cap-dependent translation. These findings not only provide new insights into the mechanisms underlying paraptosis, but also shed light on a potential approach to enhance GBM treatment.
癌症是全球第二大致死原因。目前基于多药物化疗和/或放射治疗方案的治疗策略已经在某些情况下提高了总生存率。然而，癌细胞对细胞凋亡的抵抗经常发生，并且其发生被认为是导致治疗失败的原因之一。因此，非凋亡性细胞死亡机制已成为研究的热点，人们希望它们能够绕过肿瘤细胞的耐药性。多形性胶质母细胞瘤（GBM）是一种 4 级星形细胞瘤，是成人中最常见的脑肿瘤，死亡率很高。我们报告称，小分子环孢素结合抑制剂 NIM811 可诱导 GBM 细胞发生灾难性空泡化和细胞死亡。这些独特的特征与许多已知的细胞死亡途径不同，与一种称为 Paraptosis 的不完全定义的细胞死亡机制有关。我们发现，NIM811 诱导的 Paraptosis 是由于未解决的内质网应激。异常上调的蛋白质翻译导致内质网中错误折叠或未折叠的蛋白质堆积，而在 NIM811 长期治疗期间，促生存自噬和 UPR 信号被关闭。尽管已有人声称环肽抑制 Paraptosis，但实际上我们发现它只是暂时延迟了空泡形成，但在长期内实际上增强了 Paraptosis 细胞死亡。另一方面，mTOR 抑制剂通过维持自噬和 UPR 来挽救细胞免受 NIM811 诱导的 Paraptosis，但特异性地抑制帽依赖性翻译。这些发现不仅为 Paraptosis 的机制提供了新的见解，而且为增强 GBM 治疗提供了一种潜在的方法。
