title: 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.affiliation: Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
authors.forename: Michela
authors.initials: M
authors.lastname: Marani
authors.forename: Olivier
authors.initials: O
authors.lastname: Pardo
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Warne
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelly
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
authors.forename: Frédéric
authors.initials: F
authors.lastname: Elustondo
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang
authors.forename: Jillian
authors.initials: J
authors.lastname: Temple
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Ahmed
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.forename: Barbara
authors.initials: B
authors.lastname: Nicke
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism*; D043171:Chromosomal Instability; D015536:Down-Regulation; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008938:Mitosis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D011123:Polyploidy; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D002518:Ceramides; D034741:RNA, Small Interfering; D011494:Protein Kinases; C119090:CERT1 protein, human; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel