Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, PR China.
Eur J Cancer. 2011 Jul;47(10):1585-94. doi: 10.1016/j.ejca.2011.01.019. Epub 2011 Mar 1.
Mechanisms of cisplatin resistance in cancer cells are not fully understood. Here, we show a critical role for the ubiquitin-binding protein p62/SQSTM1 in cisplatin resistance in human ovarian cancer cells (HOCCs). Specifically, we found that cisplatin-resistant SKOV3/DDP cells express much higher levels of p62 than do cisplatin-sensitive SKOV3 cells. The protein p62 binds ubiquitinated proteins for transport to autophagic degradation, reducing apoptosis induced by endoplasmic reticulum (ER) stress in SKOV3/DDP cells. Knockdown of p62 or inhibition of autophagy using 3-methyladenine resensitises SKOV3/DDP cells to cisplatin. Collectively, our data indicate that p62 acts as a receptor or adaptor for autophagic degradation of ubiquitinated proteins, and plays an important role in preventing ER stress-induced apoptosis, leading to cisplatin resistance in HOCCs.
癌细胞中顺铂耐药的机制尚不完全清楚。在这里，我们表明泛素结合蛋白 p62/SQSTM1 在人卵巢癌细胞（HOCCs）中的顺铂耐药中起关键作用。具体来说，我们发现顺铂耐药的 SKOV3/DDP 细胞比顺铂敏感的 SKOV3 细胞表达更高水平的 p62。蛋白 p62 结合泛素化蛋白进行运输到自噬降解，减少内质网（ER）应激诱导的 SKOV3/DDP 细胞凋亡。p62 的敲低或使用 3-甲基腺嘌呤抑制自噬使 SKOV3/DDP 细胞对顺铂敏感。总之，我们的数据表明 p62 作为泛素化蛋白自噬降解的受体或衔接蛋白发挥作用，在防止 ER 应激诱导的细胞凋亡中起重要作用，导致 HOCCs 中的顺铂耐药。
