title: Progesterone receptor activation is required for folic acid-induced anti-proliferation in colorectal cancer cell lines.
abstract: Previously, we demonstrated that folic acid (FA) could inhibit proliferation of colorectal cancer cell lines through activating the folate receptor (FR)α/cSrc/ERK1/2/NFκB/p53 pathway and anti-COLO-205 tumor growth in vivo. Since we recently also demonstrated that female sex hormones could affect the FA's action in regulating endothelial cell proliferation and migration, the aim of this study was to investigate the effect of progesterone (P4) on the FA-induced anti-proliferation in colorectal cancer cells. Treatment with FA significantly reduced the proliferation of the P4 receptor (PR)-positive colon cancer cell lines, COLO-205, HT-29 and LoVo, but did not significantly affect the proliferation of the PR-negative colon cancer cell lines, HCT116 and DLD-1. Pre-treatment with Org 31710, a PR specific antagonist, abolished the FA-induced proliferation inhibition and activation in the signaling pathway involved in regulating proliferation inhibition in these PR positive colorectal cancer cell lines. The involvement of PR in the FA-induced activation of cSrc and up-regulations in cell cycle inhibitory proteins (p21, p27 and p53) was confirmed by knock-down of PR expression using the siRNA technique. Importantly, we show direct protein interaction between FR and PR in COLO-205. Moreover, treatment with FA induced PR activation in COLO-205. Taken together, these data suggest that FA induced proliferation inhibition in colon cancer cells through activation of PR. This finding might explain some of the controversies of FA's effects on cancer growth and provide valuable reference for clinical applications of FA in treating colorectal cancer.
authors.affiliation: Graduate Institutes of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Kuo
authors.affiliation: Graduate Institutes of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Cancer Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan. Electronic address: wslee@tmu.edu.tw.
authors.forename: Wen-Sen
authors.initials: WS
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D058973:Folate Receptors, GPI-Anchored / Q000819:agonists / Q000378:metabolism; D005492:Folic Acid / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011980:Receptors, Progesterone / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D058973:Folate Receptors, GPI-Anchored; D016376:Oligonucleotides, Antisense; D011980:Receptors, Progesterone; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C101118:progesterone receptor A; C097314:progesterone receptor B; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005492:Folic Acid
keywords: COLO-205; Folate receptor; Immunoprecipitation; Small interfering RNA; cSrc