Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs.
- Abstract:
- 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.
- Authors:
- C Swanton, M Marani, O Pardo, PH Warne, G Kelly, E Sahai, F Elustondo, J Chang, J Temple, AA Ahmed, JD Brenton, J Downward, B Nicke
- Journal:
- Cancer Cell
- Citation info:
- 11(6):498-512
- Publication date:
- 1st Jun 2007
- Full text
- DOI