title: Isorhamnetin suppresses skin cancer through direct inhibition of MEK1 and PI3-K.
abstract: 3'-Methoxy-3,4',5,7-tetrahydroxyflavone (isorhamnetin) is a plant flavonoid that occurs in fruits and medicinal herbs. Isorhamnetin exerts anticancer effects, but the underlying molecular mechanism for the chemopreventive potential of isorhamnetin remains unknown. Here, we report anti-skin cancer effects of isorhamnetin, which inhibited epidermal growth factor (EGF)-induced neoplastic cell transformation. It also suppressed anchorage-dependent and -independent growth of A431 human epithelial carcinoma cells. Isorhamnetin attenuated EGF-induced COX-2 expression in JB6 and A431 cells. In an in vivo mouse xenograft using A431 cells, isorhamnetin reduced tumor growth and COX-2 expression. The EGF-induced phosphorylation of extracellular signal-regulated kinases, p90 and p70 ribosomal S6 kinases, and Akt was suppressed by isorhamnetin. In vitro and ex vivo kinase assay data showed that isorhamnetin inhibited the kinase activity of MAP (mitogen-activated protein)/ERK (extracellular signal regulated kinase) kinase (MEK) 1 and PI3-K (phosphoinositide 3-kinase) and the inhibition was due to direct binding with isorhamnetin. Notably, isorhamnetin bound directly to MEK1 in an ATP-noncompetitive manner and to PI3-K in an ATP-competitive manner. This report is the first mechanistic study identifying a clear molecular target for the anticancer activity of isorhamnetin. Overall, these results indicate that isorhamnetin has potent anticancer activity and it primarily targets MEK and PI3-K, which might contribute to the chemopreventive potential of certain foods.
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA. zgdong@hi.umn.edu
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Dong-Eun
authors.initials: DE
authors.lastname: Lee
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Joe Eun
authors.initials: JE
authors.lastname: Son
authors.forename: Sang Kwon
authors.initials: SK
authors.lastname: Seo
authors.forename: Jixia
authors.initials: J
authors.lastname: Li
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Madhusoodanan
authors.initials: M
authors.lastname: Mottamal
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000187:drug effects; D005260:Female; D044948:Flavonols / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011794:Quercetin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms / Q000201:enzymology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051546:Cyclooxygenase 2; D044948:Flavonols; D048369:MAP Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011794:Quercetin; C047368:3-methylquercetin