title: Piceatannol, a hydroxystilbene natural product, stabilizes HIF-1α protein by inhibiting HIF prolyl hydroxylase.
abstract: To investigate the mechanisms underlying the biological activity of piceatannol (PCT), a hydroxystilbene natural product that has anti-colitic properties, we examined whether PCT could modulate hypoxia-inducible factor (HIF)-1 activity in human colon carcinoma cells. PCT induced HIF-1α protein, leading to induction of its target gene products, vascular endothelial growth factor and heme oxygenase-1, which are involved in amelioration of colitis. PCT induction of HIF-1α resulted from HIF-1α protein stabilization, which occurred through inhibition of HIF-prolyl hydroxylase-2 (HPH-2). PCT inhibition of HPH-2 was reversed by addition of ascorbate, a cofactor of HPH-2, but not the cosubstrate, 2-ketoglutarate, to the reaction mixture of an in vitro von Hippel-Lindau (VHL) capture assay, and pretreatment with ascorbate abrogated PCT induction of cellular HIF-1α. Moreover, PCT prevented hydroxylation of cellular HIF-1α and attenuated coimmunoprecipitation of Flag-VHL protein and HA-HIF-1α over-expressed in human embryonic kidney 293 cells. Structural analysis using derivatives of PCT revealed that the catechol moiety in PCT was required for the stabilization of HIF-1α protein. Taken together, PCT activation of HIF-1 resulting from inhibition of HPH-2 may be a molecular mechanism for an anti-colitic effect of the natural product.
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Soohwan
authors.initials: S
authors.lastname: Yum
authors.forename: Hea-Jeong
authors.initials: HJ
authors.lastname: Doh
authors.forename: Sungchae
authors.initials: S
authors.lastname: Hong
authors.forename: Seongkeun
authors.initials: S
authors.lastname: Jeong
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.forename: Misun
authors.initials: M
authors.lastname: Park
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
mesh_terms: D001205:Ascorbic Acid / Q000494:pharmacology; D045744:Cell Line, Tumor; D003092:Colitis / Q000188:drug therapy / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects* / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D013267:Stilbenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; C041525:3,3',4,5'-tetrahydroxystilbene; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051547:Heme Oxygenase-1; D001205:Ascorbic Acid