title: LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1alpha via upregulation of VHL in a colon cancer cell line.
abstract: Hypoxia-inducible factor HIF-1 is responsible for radiation resistance and poor prognosis in cancer therapy. As part of our drug discovery program, a novel HIF inhibitor, LW6, was identified as a small compound that inhibits the accumulation of HIF-1alpha. We found that LW6 decreased HIF-1alpha protein expression without affecting HIF-1beta expression. MG132, a proteasome inhibitor, protected HIF-1alpha from LW6-induced proteasomal degradation, indicating that LW6 affects the stability of the HIF-1alpha protein. We found that LW6 promoted the degradation of wild type HIF-1alpha, but not of a DM-HIF-1alpha with modifications of P402A and P564A, at hydroxylation sites in the oxygen-dependent degradation domain (ODDD). LW6 did not affect the activity of prolyl hydroxylase (PHD), but induced the expression of von Hippel-Lindau (VHL), which interacts with prolyl-hydroxylated HIF-1alpha for proteasomal degradation. In the presence of LW6, knockdown of VHL did not abolish HIF-1alpha protein accumulation, indicating that LW6 degraded HIF-1alpha via regulation of VHL expression. In mice carrying xenografts of human colon cancer HCT116 cells, LW6 demonstrated strong anti-tumor efficacy in vivo and caused a decrease in HIF-1alpha expression in frozen-tissue immunohistochemical staining. These data suggest that LW6 may be valuable in the development of a HIF-1alpha inhibitor for cancer treatment.
authors.affiliation: Dongguk University-Seoul, Seoul, 100-715, Republic of Korea.
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Kang
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Yinglan
authors.initials: Y
authors.lastname: Jin
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Chung
authors.forename: Hwan-Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.forename: Moo Rim
authors.initials: MR
authors.lastname: Kang
authors.forename: Myung Kyu
authors.initials: MK
authors.lastname: Lee
authors.forename: Kyung Bin
authors.initials: KB
authors.lastname: Song
authors.forename: Eun-Gyeong
authors.initials: EG
authors.lastname: Yang
authors.forename: Jung-Jun
authors.initials: JJ
authors.lastname: Lee
authors.forename: Misun
authors.initials: M
authors.lastname: Won
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002460:Cell Line; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010100:Oxygen / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000378:metabolism
chemical_list: C497396:ARNT protein, human; D000083:Acetanilides; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000607696:LW6 compound; D011506:Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D011393:Procollagen-Proline Dioxygenase; D046988:Proteasome Endopeptidase Complex; D000218:Adamantane; D010100:Oxygen