title: The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis.
abstract: Anti-mitotic agents such as paclitaxel and docetaxel are widely used for the treatment of breast, ovarian and lung cancers. Although paclitaxel induces apoptosis, this drug also modulates autophagy. How autophagy affects paclitaxel activity, is unclear. We discovered that paclitaxel inhibited autophagy through two distinct mechanisms dependent on cell cycle stage. In mitotic cells, paclitaxel blocked activation of the class III phosphatidyl inositol 3 kinase, Vps34, a critical initiator of autophagosome formation. In non-mitotic paclitaxel-treated cells, autophagosomes were generated but their movement and maturation was inhibited. Chemically or genetically blocking autophagosome formation diminished paclitaxel-induced cell death suggesting that autophagosome accumulation sensitized cells to paclitaxel toxicity. In line with these observations, we identified that primary breast tumors that expressed diminished levels of autophagy-initiating genes were resistant to taxane therapy, identifying possible mechanisms and prognostic markers of clinical chemotherapeutic resistance.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: R A
authors.initials: RA
authors.lastname: Veldhoen
authors.forename: S L
authors.initials: SL
authors.lastname: Banman
authors.forename: D R
authors.initials: DR
authors.lastname: Hemmerling
authors.forename: R
authors.initials: R
authors.lastname: Odsen
authors.forename: T
authors.initials: T
authors.lastname: Simmen
authors.forename: A J
authors.initials: AJ
authors.lastname: Simmonds
authors.forename: D A
authors.initials: DA
authors.lastname: Underhill
authors.forename: I S
authors.initials: IS
authors.lastname: Goping
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D058546:Class III Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D058546:Class III Phosphatidylinositol 3-Kinases; D017239:Paclitaxel