Program in Molecular Biology and Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, 110 East Warren Ave., Detroit, MI 48201, USA.
Biochem Biophys Res Commun. 2010 Apr 9;394(3):600-5. doi: 10.1016/j.bbrc.2010.03.029. Epub 2010 Mar 7.
The mechanism of cisplatin resistance in cancer cells is not fully understood. Here, we show that the Akt/mTOR survival pathway plays an important role in cisplatin resistance in human ovarian cancer cells. Specifically, we found that cisplatin treatment activates the Akt/mTOR survival pathway and that inhibition of this pathway by the PI3K inhibitor LY294002 or knockdown of Akt sensitizes ovarian cancer cells to cisplatin. Furthermore, we generated cisplatin-resistant cells and found that resistant cells express a higher level of activated Akt as compared to their cisplatin sensitive counterparts. Importantly, inhibition of Akt or mTOR sensitized resistant cells to cisplatin-induced apoptosis. Taken together, our data indicate that activation of the Akt/mTOR pathway prevents cisplatin-induced apoptosis, leading to cisplatin resistance. Therefore, our study suggests that cisplatin resistance can be overcome by targeting the Akt/mTOR survival pathway in human ovarian cancer cells.
顺铂耐药的机制在癌细胞中尚未完全阐明。在这里，我们表明 Akt/mTOR 生存途径在人卵巢癌细胞的顺铂耐药中发挥着重要作用。具体而言，我们发现顺铂处理激活了 Akt/mTOR 生存途径，并且通过 PI3K 抑制剂 LY294002 或 Akt 的敲低抑制该途径使卵巢癌细胞对顺铂敏感。此外，我们生成了顺铂耐药细胞，并发现与顺铂敏感的细胞相比，耐药细胞表达更高水平的活化 Akt。重要的是，抑制 Akt 或 mTOR 使耐药细胞对顺铂诱导的细胞凋亡敏感。总之，我们的数据表明 Akt/mTOR 途径的激活可防止顺铂诱导的细胞凋亡，从而导致顺铂耐药。因此，我们的研究表明，通过靶向人卵巢癌细胞中的 Akt/mTOR 生存途径可以克服顺铂耐药性。
