title: Folic acid inhibits COLO-205 colon cancer cell proliferation through activating the FRα/c-SRC/ERK1/2/NFκB/TP53 pathway: in vitro and in vivo studies.
abstract: To investigate the molecular mechanism underlying folic acid (FA)-induced anti-colon caner activity, we showed that FA caused G0/G1 arrest in COLO-205. FA activated the proto-oncogene tyrosine-protein kinase Src (c-SRC)-mediated signaling pathway to enhance nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) nuclear translocation and binding onto the tumor protein p53 (TP53) gene promoter, and up-regulated expressions of TP53, cyclin-dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). Knock-down of TP53 abolished FA-induced increases in the levels of CDKN1A and CDKN1B protein and G0/G1 arrest in COLO-205. Knock-down of folate receptor alpha (FRα) abolished FA-induced activations in the c-SRC-mediated pathway and increases in the levels of CDKN1A, CDKN1B and TP53 protein. These data suggest that FA inhibited COLO-205 proliferation through activating the FRα/c-SRC/mitogen-activated protein kinase 3/1 (ERK1/2)/NFκB/TP53 pathway-mediated up-regulations of CDKN1A and CDKN1B protein. In vivo studies demonstrated that daily i.p. injections of FA led to profound regression of the COLO-205 tumors and prolong the lifespan. In these tumors, the levels of CDKN1A, CDKN1B and TP53 protein were increased and von willebrand factor (VWF) protein levels were decreased. These findings suggest that FA inhibits COLO-205 colon cancer growth through anti-cancer cell proliferation and anti-angiogenesis.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Kuo
authors.affiliation: School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chieh
authors.initials: C
authors.lastname: Chang
authors.affiliation: 1] Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan [2] Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan [3] Cancer Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan.
authors.forename: Wen-Sen
authors.initials: WS
authors.lastname: Lee
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005492:Folic Acid / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C000715470:MAS1 protein, human; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005492:Folic Acid; D016392:Proto-Oncogene Proteins pp60(c-src)