Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China.
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan, PR China.
Free Radic Biol Med. 2022 Nov 20;193(Pt 1):95-107. doi: 10.1016/j.freeradbiomed.2022.10.271. Epub 2022 Oct 13.
Circulating tumor cells (CTCs) acquire enhanced anti-anoikis abilities after experiencing flow shear stress in the circulatory system. Our previous study demonstrated that low shear stress (LSS) promotes anoikis resistance of human breast carcinoma cells via caveolin-1 (Cav-1)-dependent extrinsic and intrinsic apoptotic pathways. However, the underlying mechanism how LSS enhanced Cav-1 expression in suspended cancer cells remains unclear. Herein, we found that LSS induced redox signaling was involved in the regulation of Cav-1 level and anoikis resistance in suspension cultured cancer cells. Exposure of human breast carcinoma MDA-MB-231 cells to LSS (2 dyn/cm) markedly induced ROS and NO generation, which promoted the cell viability and reduced the cancer cell apoptosis. Furthermore, ROS and NO scavenging inhibited the upregulation of Cav-1 by interfering ubiquitination, and suppressed the anoikis resistance of suspended tumor cells. These findings provide new insight into the mechanism by which LSS-stimulated ROS and NO generation increases Cav-1 stabilization in suspended cancer cells through inhibition of ubiquitination and proteasomal degradation, which could be a potential target for therapy of metastatic tumors.
循环肿瘤细胞（CTCs）在循环系统中经历流动切应力后获得增强的抗失巢凋亡能力。我们之前的研究表明，低切应力（LSS）通过质膜窖蛋白-1（Cav-1）依赖性外在和内在凋亡途径促进人乳腺癌细胞的抗失巢凋亡。然而，LSS 如何增强悬浮癌细胞中 Cav-1 表达的潜在机制尚不清楚。在此，我们发现 LSS 诱导的氧化还原信号参与了悬浮培养癌细胞中 Cav-1 水平和抗失巢凋亡的调节。将人乳腺癌 MDA-MB-231 细胞暴露于 LSS（2 dyn/cm）可显著诱导 ROS 和 NO 的产生，这促进了细胞活力并减少了癌细胞凋亡。此外，ROS 和 NO 的清除通过干扰泛素化抑制了 Cav-1 的上调，并抑制了悬浮肿瘤细胞的抗失巢凋亡。这些发现为 LSS 刺激的 ROS 和 NO 生成通过抑制泛素化和蛋白酶体降解增加悬浮癌细胞中 Cav-1 稳定性的机制提供了新的见解，这可能成为转移性肿瘤治疗的潜在靶点。
Zotero 插件