Swanton Charles, Marani Michela, Pardo Olivier, Warne Patricia H, Kelly Gavin, Sahai Erik, Elustondo Frédéric, Chang Jenny, Temple Jillian, Ahmed Ahmed A, Brenton James D, Downward Julian, Nicke Barbara
Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Cancer Cell. 2007 Jun;11(6):498-512. doi: 10.1016/j.ccr.2007.04.011.
Cytotoxic drug resistance is a major cause of cancer treatment failure. We report an RNA interference screen to identify genes influencing sensitivity of different cancer cell types to chemotherapeutic agents. A set of genes whose targeting leads to resistance to paclitaxel is identified, many of which are involved in the spindle assembly checkpoint. Silencing these genes attenuates paclitaxel-induced mitotic arrest and induces polyploidy in the absence of drug. We also identify a ceramide transport protein, COL4A3BP or CERT, whose downregulation sensitizes cancer cells to multiple cytotoxic agents, potentiating endoplasmic reticulum stress. COL4A3BP expression is increased in drug-resistant cell lines and in residual tumor following paclitaxel treatment of ovarian cancer, suggesting that it could be a target for chemotherapy-resistant cancers.
细胞毒性药物耐药性是癌症治疗失败的主要原因。我们报告了一项RNA干扰筛选，以鉴定影响不同癌细胞类型对化疗药物敏感性的基因。鉴定出一组其靶向作用导致对紫杉醇耐药的基因，其中许多基因参与纺锤体组装检查点。沉默这些基因可减弱紫杉醇诱导的有丝分裂停滞，并在无药物的情况下诱导多倍体形成。我们还鉴定出一种神经酰胺转运蛋白，即Ⅳ型胶原A3结合蛋白（COL4A3BP）或CERT，其下调使癌细胞对多种细胞毒性药物敏感，增强内质网应激。在耐药细胞系以及卵巢癌患者接受紫杉醇治疗后的残留肿瘤中，COL4A3BP表达增加，这表明它可能是化疗耐药性癌症的一个靶点。
