World Class University Biomodulation Major, Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea.
PLoS One. 2013 Sep 23;8(9):e75455. doi: 10.1371/journal.pone.0075455. eCollection 2013.
Resistance to cisplatin-based therapy is a major cause of treatment failure in human ovarian cancer. A better understanding of the mechanisms of cisplatin resistance will offer new insights for novel therapeutic strategies for this deadly disease. Akt and p53 are determinants of cisplatin sensitivity. Rictor is a component of mTOR protein kinase complex 2, which is required for Akt phosphorylation (Ser473) and full activation. However, the precise role of rictor and the relationship between rictor and p53 in cisplatin resistance remains poorly understood. Here, using sensitive wild-type p53 (OV2008 and A2780s), resistant wild-type p53 (C13* and OVCAR433), and p53 compromised (A2780cp, OCC1, and SKOV-3) ovarian cancer cells, we have demonstrated that (i) rictor is a determinant of cisplatin resistance in chemosensitive human ovarian cancer cells; (ii) cisplatin down-regulates rictor content by caspase-3 cleavage and proteasomal degradation; (iii) rictor down-regulation sensitizes chemo-resistant ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner; (iv) rictor suppresses cisplatin-induced apoptosis and confers resistance by activating and stabilizing Akt. These findings extend current knowledge on the molecular and cellular basis of cisplatin resistance and provide a rationale basis for rictor as a potential therapeutic target for chemoresistant ovarian cancer.
顺铂耐药是人类卵巢癌治疗失败的主要原因。更好地了解顺铂耐药的机制将为这种致命疾病的新治疗策略提供新的见解。Akt 和 p53 是顺铂敏感性的决定因素。Rictor 是 mTOR 蛋白激酶复合物 2 的一个组成部分，该复合物对于 Akt 的磷酸化（Ser473）和完全激活是必需的。然而，Rictor 的精确作用以及 Rictor 与 p53 之间在顺铂耐药中的关系仍知之甚少。在这里，我们使用敏感的野生型 p53（OV2008 和 A2780s）、耐药的野生型 p53（C13* 和 OVCAR433）和 p53 功能受损（A2780cp、OCC1 和 SKOV-3）卵巢癌细胞，证明了：（i）Rictor 是化学敏感的人类卵巢癌细胞顺铂耐药的决定因素；（ii）顺铂通过 caspase-3 切割和蛋白酶体降解下调 Rictor 含量；（iii）Rictor 下调以依赖 p53 的方式使耐化疗的卵巢癌细胞对顺铂诱导的细胞凋亡敏感；（iv）Rictor 通过激活和稳定 Akt 抑制顺铂诱导的细胞凋亡并赋予耐药性。这些发现扩展了关于顺铂耐药的分子和细胞基础的现有知识，并为 Rictor 作为化疗耐药卵巢癌的潜在治疗靶点提供了合理的依据。
