Critical role of PPARγ in myeloid-derived suppressor cellstimulated cancer cell proliferation and metastasis

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Lysosomal acid lipase (LAL) is a key enzyme controlling neutral lipid metabolic signaling in myeloid-derived suppressor cells (MDSCs). MDSCs from LAL-deficient (lal-/-) mice directly stimulate cancer cell proliferation. PPARf ligand treatment inhibited lal-/- MDSCs stimulation of tumor cell growth and metastasis in vivo, and tumor cell proliferation and migration in vitro. In addition, PPARγ ligand treatment impaired lal-/- MDSCs transendothelial migration, and differentiation from lineage-negative cells. The corrective effects of PPARγ ligand on lal-/- MDSCs functions were mediated by regulating the mammalian target of rapamycin (mTOR) pathway, and subsequently blocking MDSCs ROS overproduction. Furthermore, in the myeloid-specific dominant-negative PPARγ (dnPPARγ) overexpression bitransgenic mouse model, tumor growth and metastasis were enhanced, and MDSCs from these mice stimulated tumor cell proliferation and migration. MDSCs with dnPPARγ overexpression showed increased transendothelial migration, overactivation of the mTOR pathway, and ROS overproduction. These results indicate that PPARγ plays a critical role in neutral lipid metabolic signaling controlled by LAL, which provides a mechanistic basis for clinically targeting MDSCs to reduce the risk of cancer proliferation, growth and metastasis.

Original languageEnglish (US)
Pages (from-to)1529-1543
Number of pages15
JournalOncotarget
Volume7
Issue number2
DOIs
StatePublished - 2016

Keywords

  • Lipid metabolic signaling
  • Lysosomal acid lipase
  • Myeloid-derived suppressor cells
  • Peroxisome proliferator-activated

ASJC Scopus subject areas

  • Oncology

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