title: mTOR inhibition by everolimus in childhood acute lymphoblastic leukemia induces caspase-independent cell death.
abstract: Increasingly, anti-cancer medications are being reported to induce cell death mechanisms other than apoptosis. Activating alternate death mechanisms introduces the potential to kill cells that have defects in their apoptotic machinery, as is commonly observed in cancer cells, including in hematological malignancies. We, and others, have previously reported that the mTOR inhibitor everolimus has pre-clinical efficacy and induces caspase-independent cell death in acute lymphoblastic leukemia cells. Furthermore, everolimus is currently in clinical trial for acute lymphoblastic leukemia. Here we characterize the death mechanism activated by everolimus in acute lymphoblastic leukemia cells. We find that cell death is caspase-independent and lacks the morphology associated with apoptosis. Although mitochondrial depolarization is an early event, permeabilization of the outer mitochondrial membrane only occurs after cell death has occurred. While morphological and biochemical evidence shows that autophagy is clearly present it is not responsible for the observed cell death. There are a number of features consistent with paraptosis including morphology, caspase-independence, and the requirement for new protein synthesis. However in contrast to some reports of paraptosis, the activation of JNK signaling was not required for everolimus-induced cell death. Overall in acute lymphoblastic leukemia cells everolimus induces a cell death that resembles paraptosis.
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW, Australia.
authors.forename: Rana
authors.initials: R
authors.lastname: Baraz
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Cisterne
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW, Australia.
authors.forename: Philip O
authors.initials: PO
authors.lastname: Saunders
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Hewson
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW, Australia.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Thien
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW, Australia.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW, Australia.
authors.forename: Jordan
authors.initials: J
authors.lastname: Basnett
authors.affiliation: Department of Haematology, Westmead Hospital, Westmead, NSW, Australia.
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bradstock
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW, Australia.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bendall
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000068338:Everolimus; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020169:Caspases; D020123:Sirolimus