Division of Genome Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
Sci Rep. 2022 Jul 7;12(1):11533. doi: 10.1038/s41598-022-15673-x.
The unfolded protein response (UPR) is an adaptive stress response pathway that is essential for cancer cell survival under endoplasmic reticulum stress such as during glucose starvation. In this study, we identified spautin-1, an autophagy inhibitor that suppresses ubiquitin-specific peptidase 10 (USP10) and USP13, as a novel UPR inhibitor under glucose starvation conditions. Spautin-1 prevented the induction of UPR-associated proteins, including glucose-regulated protein 78, activating transcription factor 4, and a splicing variant of x-box-binding protein-1, and showed preferential cytotoxicity in glucose-starved cancer cells. However, USP10 and USP13 silencing and treatment with other autophagy inhibitors failed to result in UPR inhibition and preferential cytotoxicity during glucose starvation. Using transcriptome and chemosensitivity-based COMPARE analyses, we identified a similarity between spautin-1 and mitochondrial complex I inhibitors and found that spautin-1 suppressed the activity of complex I extracted from isolated mitochondria. Our results indicated that spautin-1 may represent an attractive mitochondria-targeted seed compound that inhibits the UPR and cancer cell survival during glucose starvation.
未折叠蛋白反应 (UPR) 是一种适应性应激反应途径，对于内质网应激下的癌细胞存活至关重要，例如在葡萄糖饥饿期间。在这项研究中，我们鉴定了 spautin-1，一种自噬抑制剂，可抑制泛素特异性肽酶 10 (USP10) 和 USP13，作为葡萄糖饥饿条件下的新型 UPR 抑制剂。Spautin-1 可防止 UPR 相关蛋白的诱导，包括葡萄糖调节蛋白 78、激活转录因子 4 和 X 盒结合蛋白-1 的剪接变体，并在葡萄糖饥饿的癌细胞中表现出优先的细胞毒性。然而，USP10 和 USP13 的沉默以及其他自噬抑制剂的处理未能导致葡萄糖饥饿期间 UPR 抑制和优先的细胞毒性。使用转录组和基于化疗敏感性的 COMPARE 分析，我们发现 spautin-1 与线粒体复合物 I 抑制剂之间存在相似性，并发现 spautin-1 抑制了从分离的线粒体中提取的复合物 I 的活性。我们的结果表明，spautin-1 可能代表一种有吸引力的靶向线粒体的种化合物，可抑制葡萄糖饥饿期间的 UPR 和癌细胞存活。
