title: PPAR-delta promotes survival of chronic lymphocytic leukemia cells in energetically unfavorable conditions.
abstract: Targeting the mechanisms that allow chronic lymphocytic leukemia (CLL) cells to survive in harsh cancer microenvironments should improve patient outcomes. The nuclear receptor peroxisome proliferator activated receptor delta (PPARδ) sustains other cancers, and in silico analysis showed higher PPARD expression in CLL cells than normal lymphocytes and other hematologic cancers. A direct association was found between PPARδ protein levels in CLL cells and clinical score. Transgenic expression of PPARδ increased the growth and survival of CD5+Daudi cells and primary CLL cells in stressful conditions including exhausted tissue culture media, low extracellular glucose, hypoxia and exposure to cytotoxic drugs. Glucocorticoids and synthetic PPARδ agonists up-regulated PPARD expression and also protected Daudi and primary CLL cells from metabolic stressors. Survival in low glucose was related to increased antioxidant expression, substrate utilization and mitochondrial performance, and was reversed by genetic deletion and synthetic PPARδ antagonists. These findings suggest PPARδ conditions CLL cells to survive in harsh microenvironmental conditions by reducing oxidative stress and increasing metabolic efficiency. Targeting PPARδ may be beneficial in the treatment of CLL.
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: L
authors.initials: L
authors.lastname: Sun
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.|Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: S E
authors.initials: SE
authors.lastname: Dunn
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Iorio
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: R A
authors.initials: RA
authors.lastname: Screaton
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Immunology, University of Toronto, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Department of Medical Oncology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: D E
authors.initials: DE
authors.lastname: Spaner
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008660:Metabolism / Q000187:drug effects; D058990:Molecular Targeted Therapy; D018384:Oxidative Stress / Q000187:drug effects; D047494:PPAR delta / Q000032:analysis* / Q000494:pharmacology
chemical_list: D047494:PPAR delta