Wang Juan, Wu Gen Sheng
From the Departments of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201.
From the Departments of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201
J Biol Chem. 2014 Jun 13;289(24):17163-73. doi: 10.1074/jbc.M114.558288. Epub 2014 May 2.
Cisplatin-based treatment is the first line chemotherapy for several cancers including ovarian cancer. The development of cisplatin resistance results in treatment failure, but the underlying mechanisms are not fully understood. Here we show that the induction of autophagy plays an important role in cisplatin resistance in ovarian cancer cells. Specifically, we show that cisplatin resistance is correlated with autophagy induction in a panel of ovarian cancer cells but not in immortalized human ovarian surface epithelial cells. Mechanistically, cisplatin treatment activates ERK and subsequently promotes autophagy. The inhibition of ERK activation with MEK inhibitors or knockdown of ERK expression with siRNA decreases cisplatin-induced autophagy and subsequently sensitizes ovarian cancer cells to cisplatin-induced apoptosis. In ovarian cancer cells that have developed acquired cisplatin resistance, both ERK activation and autophagy induction are increased. Importantly, knockdown of ERK or inhibition of autophagy promotes cisplatin-induced apoptosis in acquired cisplatin-resistant cells. Collectively, our data indicate that ERK-mediated autophagy can lead to cisplatin resistance and suggest that cisplatin resistance can be overcome by inhibition of autophagy in ovarian cancer cells.
基于顺铂的治疗是包括卵巢癌在内的几种癌症的一线化疗方法。顺铂耐药性的产生导致治疗失败，但其潜在机制尚未完全明确。在此，我们表明自噬的诱导在卵巢癌细胞对顺铂的耐药性中起重要作用。具体而言，我们发现顺铂耐药性与一组卵巢癌细胞中的自噬诱导相关，但在永生化的人卵巢表面上皮细胞中则不然。从机制上讲，顺铂治疗激活ERK，随后促进自噬。用MEK抑制剂抑制ERK激活或用siRNA敲低ERK表达可降低顺铂诱导的自噬，随后使卵巢癌细胞对顺铂诱导的凋亡敏感。在已获得顺铂耐药性的卵巢癌细胞中，ERK激活和自噬诱导均增加。重要的是，敲低ERK或抑制自噬可促进顺铂诱导的获得性顺铂耐药细胞凋亡。总体而言，我们的数据表明ERK介导的自噬可导致顺铂耐药，并提示通过抑制卵巢癌细胞中的自噬可克服顺铂耐药性。
