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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.

Original publication

DOI

10.1016/j.ccr.2007.04.011

Type

Journal article

Journal

Cancer cell

Publication Date

06/2007

Volume

11

Pages

498 - 512

Keywords

Cell Line, Tumor, Cell Survival, Ceramides, Chromosomal Instability, Down-Regulation, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Female, Humans, Mitosis, Ovarian Neoplasms, Paclitaxel, Polyploidy, Protein Kinases, Protein-Serine-Threonine Kinases, RNA, Small Interfering