Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs.
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.
Swanton
Charles
C
Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Marani
Michela
M
Pardo
Olivier
O
Warne
Patricia H
PH
Kelly
Gavin
G
Sahai
Erik
E
Elustondo
Frédéric
F
Chang
Jenny
J
Temple
Jillian
J
Ahmed
Ahmed A
AA
Brenton
James D
JD
Downward
Julian
J
Nicke
Barbara
B
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
D002518:Ceramides; D034741:RNA, Small Interfering; D011494:Protein Kinases; C119090:CERT1 protein, human; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel