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Leukemia. 2017 Sep;31(9):1905-1914. doi: 10.1038/leu.2016.395. Epub 2017 Jan 4.

PPAR-delta promotes survival of chronic lymphocytic leukemia cells in energetically unfavorable conditions.

Li YJ1,2, Sun L1,2, Shi Y1, Wang G1, Wang X1,3, Dunn SE4,5, Iorio C1, Screaton RA6, Spaner DE1,4,7,8,9.

Author information

1
Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
2
Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
3
Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.
4
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
5
Toronto General Research Institute, Toronto, Ontario, Canada.
6
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
7
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
8
Department of Medical Oncology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada.
9
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

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.

PMID:
28050012
DOI:
10.1038/leu.2016.395
[Indexed for MEDLINE]

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