LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1α via upregulation of VHL in a colon cancer cell line

Title
LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1α via upregulation of VHL in a colon cancer cell line
Authors
Kyeong LeeJung Eun KangSong-Kyu ParkYinglan JinKyung-Sook ChungHwan-Mook KimKiho LeeMoo Rim KangMyung Kyu LeeKyung Bin Song양은경Jung-Jun LeeMisun Won
Keywords
HIF-1α; von-Hippel-Lindau; (aryloxyacetylamino)Benzoic acid; Prolyl hydroxylation; Hypoxia
Issue Date
2010-10
Publisher
Biochemical pharmacology
Citation
VOL 80, NO 7, 982-989
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-1α. We found that LW6 decreased HIF-1α protein expression without affecting HIF-1β expression. MG132, a proteasome inhibitor, protected HIF-1α from LW6-induced proteasomal degradation, indicating that LW6 affects the stability of the HIF-1α protein. We found that LW6 promoted the degradation of wild type HIF-1α, but not of a DM-HIF-1α 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-1α for proteasomal degradation. In the presence of LW6, knockdown of VHL did not abolish HIF-1α protein accumulation, indicating that LW6 degraded HIF-1α 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-1α expression in frozen-tissue immunohistochemical staining. These data suggest that LW6 may be valuable in the development of a HIF-1α inhibitor for cancer treatment.
URI
http://pubs.kist.re.kr/handle/201004/37864
ISSN
0006-2952
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KIST Publication > Article
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