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Transcriptional control and signal transduction, cell cycle

PPAR-delta modulates membrane cholesterol and cytokine signaling in malignant B cells

Leukemia volume 32, pages 184–193 (2018)Cite this article

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Abstract

A deeper understanding of the mechanisms that underlie aberrant signal transduction in B-cell cancers such as chronic lymphocytic leukemia (CLL) may reveal new treatment strategies. The lipid-activated nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ) accounts for a number of properties of aggressive cancers and was found to enhance Janus kinase (JAK)-mediated phosphorylation of signal transducer and activator of transcription (STAT) proteins in B lymphoma cell lines and primary CLL cells. Autocrine production of cytokines such as IL10 and interferon-beta was not increased by PPARδ but signaling responses to these cytokines were amplified and associated with increased cholesterol biosynthesis and plasma membrane levels. Plasmalemmal cholesterol and STAT phosphorylation from type 1 interferons (IFNs) were increased by PPARδ agonists, transgenes and exogenous cholesterol, and decreased by cyclodextrin, PPARD deletion and chemical PPARδ inhibitors. Functional consequences of PPARδ-mediated perturbation of IFN signaling included impaired upregulation of co-stimulatory molecules. These observations suggest PPARδ modulates signaling processes in malignant B cells in part by altering cholesterol metabolism and changes the outcomes of signaling from cytokines such as IFNs. PPARδ antagonists may have therapeutic activity as anti-leukemic signal transduction modulators.

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Acknowledgements

This work was supported by CIHR grant MOP1304, CIHR grant MOP 110952, the Leukemia and Lymphoma Society of Canada (DS), CIHR grant MOP133656 (GDF), NSFC (China) grant 81372456 and the Fund for the 8th group of Fostering Talents in Jilin Province of China JRZX8 (Y-JL). LS was supported by the China Scholarship Council (CSC 201506170134). We thank Peppi Prasit (Inception Sciences, San Diego, CA) for NXT1511 and Prof Dr Wibke E Diederich (Center for Tumor Biology and Immunology, Core Facility Medicinal Chemistry, Philipps-Universität Marburg) for DG172.

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Author notes

  1. Y-J Li and D E Spaner: Co-senior authors.

Authors and Affiliations

  1. Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada

    L Sun, Y Shi, G Wang, X Wang, S Zeng, Y-J Li & D E Spaner

  2. Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, China

    L Sun & Y-J Li

  3. Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China

    X Wang

  4. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

    S Zeng, S E Dunn & D E Spaner

  5. Toronto General Research Institute, Toronto, Ontario, Canada

    S E Dunn

  6. Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Ontario, Canada

    G D Fairn

  7. Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada

    G D Fairn

  8. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    D E Spaner

  9. Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada

    D E Spaner

  10. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    D E Spaner

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Correspondence to Y-J Li or D E Spaner.

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Sun, L., Shi, Y., Wang, G. et al. PPAR-delta modulates membrane cholesterol and cytokine signaling in malignant B cells. Leukemia 32, 184–193 (2018). https://doi.org/10.1038/leu.2017.162

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