Lee, Kyeong Kang, Jung Eun Park, Song-Kyu Jin, Yinglan Chung, Kyung-Sook Kim, Hwan-Mook Lee, Kiho Kang, Moo Rim Lee, Myung Kyu Song, Kyung Bin Yang, Eun-Gyeong Lee, Jung-Jun Won, Misun 2024-01-20T18:31:23Z 2024-01-20T18:31:23Z 2021-09-05 2010-10-01 0006-2952 https://pubs.kist.re.kr/handle/201004/131013 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-1 alpha. We found that LW6 decreased HIF-1 alpha protein expression without affecting HIF-1 beta expression. MG132, a proteasome inhibitor, protected HIF-1 alpha from LW6-induced proteasomal degradation, indicating that LW6 affects the stability of the HIF-1 alpha protein. We found that LW6 promoted the degradation of wild type HIF-1 alpha, but not of a DM-HIF-1 alpha 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-1 alpha for proteasomal degradation. In the presence of LW6, knockdown of VHL did not abolish HIF-1 alpha protein accumulation, indicating that LW6 degraded HIF-1 alpha 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-1 alpha expression in frozen-tissue immunohistochemical staining. These data suggest that LW6 may be valuable in the development of a HIF-1 alpha inhibitor for cancer treatment. (C) 2010 Elsevier Inc. All rights reserved. English PERGAMON-ELSEVIER SCIENCE LTD HYPOXIA-INDUCIBLE FACTOR-1 ARYL-HYDROCARBON RECEPTOR TUMOR-SUPPRESSOR GENE FACTOR 1-ALPHA FACTOR-I PROTEIN ALPHA IDENTIFICATION ANGIOGENESIS INDUCTION LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1 alpha via upregulation of VHL in a colon cancer cell line Article 10.1016/j.bcp.2010.06.018 1 BIOCHEMICAL PHARMACOLOGY, v.80, no.7, pp.982 - 989 BIOCHEMICAL PHARMACOLOGY 80 7 982 989 scie scopus 000281428800005 2-s2.0-77955656201 Pharmacology & Pharmacy Pharmacology & Pharmacy Article HYPOXIA-INDUCIBLE FACTOR-1 ARYL-HYDROCARBON RECEPTOR TUMOR-SUPPRESSOR GENE FACTOR 1-ALPHA FACTOR-I PROTEIN ALPHA IDENTIFICATION ANGIOGENESIS INDUCTION HIF-1 alpha von-Hippel-Lindau (aryloxyacetylamino)Benzoic acid Pro lyl hydroxylation Hypoxia