title: Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death.
abstract: Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer.
authors.affiliation: Departments of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Morgan
authors.affiliation: Departments of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: John
authors.initials: J
authors.lastname: Lynch
authors.affiliation: Departments of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.affiliation: Departments of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: Sharon
authors.initials: S
authors.lastname: Frase
authors.affiliation: Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: Ju
authors.initials: J
authors.lastname: Bao
authors.affiliation: Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Cell and Molecular Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Opferman
authors.affiliation: Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: Laura
authors.initials: L
authors.lastname: Janke
authors.affiliation: Epidemiology &Cancer Control, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Green
authors.affiliation: Epidemiology &Cancer Control, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.|Endocrinology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: Wassim
authors.initials: W
authors.lastname: Chemaitilly
authors.affiliation: Departments of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D053478:Apoptosomes / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D015122:Mercaptopurine / Q000494:pharmacology* / Q000633:toxicity; D008727:Methotrexate / Q000494:pharmacology / Q000633:toxicity; D008822:Mice, Transgenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D053478:Apoptosomes; D020169:Caspases; D015122:Mercaptopurine; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017382:Reactive Oxygen Species; C489540:Abcc4 protein, mouse