Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
Department of Pharmacy, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
Cancer Lett. 2018 Apr 10;419:116-127. doi: 10.1016/j.canlet.2018.01.045.
Chaperone-mediated autophagy (CMA) characterized by the selective degradation of target proteins has been linked with tumorigenesis in recent years. Here, we explored the function of sorting nexin 10 (SNX10), a protein involved in maintaining endosome/lysosome homeostasis, in mediating CMA activity and its impact on the progression of mouse inflammation-driven colorectal cancer. Our results revealed that SNX10 deficiency increased the activation of CMA by preventing the degradation of lysosomal LAMP-2A. In SNX10 KO cells, we disclosed that p21, a master effector in various tumor suppressor pathways, is a substrate of CMA, and decrease of p21 caused by SNX10-mediated CMA activation contributes to HCT116 cell proliferation and survival. Moreover, we found that SNX10 KO promoted tumorigenesis in the mouse colorectum which could be restored by SNX10 over-expression. Furthermore, SNX10 was remarkably down-regulated in human CRC tissues which showed the increased activity of CMA and decreased expression of p21. These findings suggest that SNX10 acts as a tumor suppressor in the mouse colorectum and drives inflammation-associated colorectal cancer by a chaperone-mediated autophagy mechanism.
伴侣蛋白介导的自噬（CMA）的特征是选择性降解靶蛋白，近年来与肿瘤发生有关。在这里，我们研究了分选连接蛋白 10（SNX10）在介导 CMA 活性及其对小鼠炎症驱动结直肠癌进展中的作用，该蛋白参与维持内体/溶酶体稳态。我们的结果表明，SNX10 缺乏通过阻止溶酶体 LAMP-2A 的降解增加了 CMA 的激活。在 SNX10 KO 细胞中，我们揭示了 p21，一种在各种肿瘤抑制途径中的主要效应因子，是 CMA 的底物，而 SNX10 介导的 CMA 激活导致的 p21 减少有助于 HCT116 细胞的增殖和存活。此外，我们发现 SNX10 KO 促进了小鼠结直肠的肿瘤发生，而 SNX10 的过表达可以恢复这种作用。此外，SNX10 在人类 CRC 组织中显著下调，其 CMA 活性增加，p21 表达减少。这些发现表明，SNX10 作为小鼠结直肠中的肿瘤抑制因子，通过伴侣蛋白介导的自噬机制驱动炎症相关结直肠癌。
