title: PPARδ deficiency disrupts hypoxia-mediated tumorigenic potential of colon cancer cells.
abstract: Peroxisome proliferator-activated receptor (PPAR) δ is highly expressed in colon epithelial cells and closely linked to colon carcinogenesis. However, the role of PPARδ 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% O2) and deferoxamine (a hypoxia mimetic) was significantly attenuated in PPARδ-deficient HCT116 colon cancer cells. Consequently, PPARδ-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 PPARδ, but not its protein expression, in HCT116 cells. Exogenous expression of p300 potentiated deferoxamine-induced PPARδ transactivation, while siRNA knockdown of p300 abolished hypoxia- and deferoxamine-induced PPARδ transactivation. PPARδ associated with p300 upon hypoxic stress as demonstrated by coimmunoprecipitation studies. PI3K inhibitors or siRNA knockdown of Akt suppressed the PPARδ transactivation induced by hypoxia and deferoxamine in HCT116 cells, leading to decreased expression of IL-8 and VEGF. Collectively, these results reveal that PPARδ 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 PPARδ transactivation induced by hypoxic stress. Our results demonstrate the positive crosstalk between PPARδ in tumor cells and the hypoxic tumor microenvironment and provide potential therapeutic targets for colon cancer.
authors.affiliation: Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, Korea.
authors.forename: Eunshil
authors.initials: E
authors.lastname: Jeong
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Koo
authors.forename: Sang Hyeon
authors.initials: SH
authors.lastname: Yeon
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Kwak
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hwang
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003106:Colon / Q000166:cytology / Q000378:metabolism; D003110:Colonic Neoplasms / Q000098:blood supply / Q000235:genetics*; D003676:Deferoxamine / Q000494:pharmacology; D050881:E1A-Associated p300 Protein / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D008264:Macrophages / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics; D047494:PPAR delta / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015533:Transcriptional Activation; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D047494:PPAR delta; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051057:Proto-Oncogene Proteins c-akt; D003676:Deferoxamine
keywords: IL-8; VEGF; colon cancer; hypoxia; peroxisome proliferator-activated receptor delta