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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.

SUBMITTER: Morgan JA

PROVIDER: S-EPMC4649703 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death.

Morgan Jessica A JA Lynch John J Panetta John C JC Wang Yao Y Frase Sharon S Bao Ju J Zheng Jie J Opferman Joseph T JT Janke Laura L Green Daniel M DM Chemaitilly Wassim W Schuetz John D JD

Scientific reports 20151118

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 ...[more]

PMID: 26576726

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Project description:OBJECTIVE:Alternative activation (M2) of adipose tissue resident macrophage (ATM) inhibits obesity-induced metabolic inflammation. The underlying mechanisms remain unclear. Recent studies have shown that dysregulated lipid homeostasis caused by increased lipolysis in white adipose tissue (WAT) in the obese state is a trigger of inflammatory responses. We investigated the role of M2 macrophages in lipotoxicity-induced inflammation. METHODS:We used microarray experiments to profile macrophage gene expression regulated by two M2 inducers, interleukin-4 (Il-4), and peroxisome proliferator-activated receptor delta/gamma (Ppar?/Ppar?) agonists. Functional validation studies were performed in bone marrow-derived macrophages and mice deprived of the signal transducer and activator of transcription 6 gene (Stat6; downstream effector of Il-4) or Ppar?/Ppar? genes (downstream effectors of Stat6). Palmitic acid (PA) and ?-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. RESULTS:Profiling of genes regulated by Il-4 or Ppar?/Ppar? agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Ppar?/Ppar? increases the susceptibility of macrophages to PA-induced cell death. NLR family pyrin domain containing 3 (Nlrp3) inflammasome activation by PA in the presence of lipopolysaccharide is also increased in Stat6-/- macrophages and to a lesser extent, in Ppar?/?-/- macrophages. In concert, ?-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Ppar?/?-/- or Stat6-/- mice. CONCLUSIONS:Our data suggest that ATM cell death is closely linked to metabolic inflammation. Within WAT where concentrations of free fatty acids fluctuate, M2 polarization regulated by the Stat6-Ppar axis enhances ATM's tolerance to lipid-mediated stress, thereby maintaining the homeostatic state.

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Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death.

Publications

Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death.

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