PPARδ Deficiency Disrupts Hypoxia-Mediated Tumorigenic Potential of Colon Cancer Cells

Peroxisome proliferator-activated receptor (PPAR) is highly expressed in colon epithelial cells and closely linked to colon carcinogenesis. However, the role of PPAR in colon cancer cells in a hypoxic tumor microenvironment is not fully understood. We found that expression of the tumor-promoting cytokines, IL-8 and VEGF, induced by hypoxia (<1% O-2) and deferoxamine (a hypoxia mimetic) was significantly attenuated in PPAR-deficient HCT116 colon cancer cells. Consequently, PPAR-knockout colon cancer cells exposed to hypoxia and deferoxamine failed to stimulate endothelial cell vascularization and macrophage migration/proliferation, whereas wild-type cells were able to induce angiogenesis and macrophage activation in response to hypoxic stress. Hypoxic stress induced transcriptional activation of PPAR, but not its protein expression, in HCT116 cells. Exogenous expression of p300 potentiated deferoxamine-induced PPAR transactivation, while siRNA knockdown of p300 abolished hypoxia- and deferoxamine-induced PPAR transactivation. PPAR associated with p300 upon hypoxic stress as demonstrated by coimmunoprecipitation studies. PI3K inhibitors or siRNA knockdown of Akt suppressed the PPAR transactivation induced by hypoxia and deferoxamine in HCT116 cells, leading to decreased expression of IL-8 and VEGF. Collectively, these results reveal that PPAR is required for hypoxic stress-mediated cytokine expression in colon cancer cells, resulting in promotion of angiogenesis, macrophage recruitment, and macrophage proliferation in the tumor microenvironment. p300 and the PI3K/Akt pathway play a role in the regulation of PPAR transactivation induced by hypoxic stress. Our results demonstrate the positive crosstalk between PPAR in tumor cells and the hypoxic tumor microenvironment and provide potential therapeutic targets for colon cancer. (c) 2014 Wiley Periodicals, Inc.