Regulators of Mitotic Arrest and Ceramide Metabolism Are Determinants of Sensitivity to Paclitaxel and Other Chemotherapeutic Drugs

Cancer Cell. 2007 Jun;11(6):498-512. doi: 10.1016/j.ccr.2007.04.011.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Ceramides / metabolism*
  • Chromosomal Instability
  • Down-Regulation
  • Drug Resistance, Multiple / genetics
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Mitosis*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism
  • Paclitaxel / pharmacology*
  • Paclitaxel / therapeutic use
  • Polyploidy
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA, Small Interfering / pharmacology

Substances

  • Ceramides
  • RNA, Small Interfering
  • Protein Kinases
  • CERT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Paclitaxel