title: Raf and PI3K are the molecular targets for the anti-metastatic effect of luteolin.
abstract: Metastases are the primary cause of human cancer deaths. Luteolin, a naturally occurring phytochemical, has chemopreventive and/or anticancer properties in several cancer cell lines. However, anti-metastatic effects of luteolin in vivo and the underlying molecular mechanisms and target(s) remain unknown. Luteolin suppresses matrix metalloproteinase (MMP)-2 and -9 activities and invasion in murine colorectal cancer CT-26 cells. Western blot and kinase assay data revealed that luteolin inhibited Raf and phosphatidylinositol 3-kinase (PI3K) activities and subsequently attenuated phosphorylation of MEK and Akt. A pull-down assay indicated that luteolin non-competitively bound with ATP to suppress Raf activity and competitively bound with ATP to inhibit PI3K activity. GW5074, a Raf inhibitor, and LY294002, a PI3K inhibitor, inhibited MMP-2 and -9 activities and invasion in CT-26 cells. An in vivo mouse study showed that oral administration (10 or 50 mg/kg) of luteolin significantly inhibited tumor nodules and tumor volume of lung metastasis induced by intravenous injection of CT-26 cells. Luteolin also inhibited MMP-9 expression and activity in CT-26-induced mouse lung tissue. These results suggest that luteolin may have considerable potential for development as an anti-metastatic agent.
authors.affiliation: WCU Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea; Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea.
authors.forename: Ho Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.forename: Joe Eun
authors.initials: JE
authors.lastname: Son
authors.forename: Mi Hyun
authors.initials: MH
authors.lastname: Oh
authors.forename: Jihoon
authors.initials: J
authors.lastname: Lee
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Kang
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy*; D047311:Luteolin / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010636:Phenols / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D048490:raf Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002867:Chromones; D007211:Indoles; D009025:Morpholines; D010636:Phenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D047311:Luteolin; C489251:5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone