YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-kappaB signaling to HIF-1alpha accumulation during hypoxia

H-L Sun; Y-N Liu; Y-T Huang; S-L Pan; D-Y Huang; J-H Guh; F-Y Lee; S-C Kuo; C-M Teng

doi:10.1038/sj.onc.1210169

YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-kappaB signaling to HIF-1alpha accumulation during hypoxia

Oncogene. 2007 Jun 7;26(27):3941-51. doi: 10.1038/sj.onc.1210169. Epub 2007 Jan 8.

Authors

H-L Sun¹, Y-N Liu, Y-T Huang, S-L Pan, D-Y Huang, J-H Guh, F-Y Lee, S-C Kuo, C-M Teng

Affiliation

¹ Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.

PMID: 17213816
DOI: 10.1038/sj.onc.1210169

Abstract

Hypoxia-inducible factor 1 (HIF-1), a transcription factor that is critical for tumor adaptation to microenvironmental stimuli, represents an attractive chemotherapeutic target. YC-1 is a novel antitumor agent that inhibits HIF-1 through previously unexplained mechanisms. In the present study, YC-1 was found to prevent HIF-1alpha and HIF-1beta accumulation in response to hypoxia or mitogen treatment in PC-3 prostate cancer cells. Neither HIF-1alpha protein half-life nor mRNA level was affected by YC-1. However, YC-1 was found to suppress the PI3K/Akt/mTOR/4E-BP pathway, which serves to regulate HIF-1alpha expression at the translational step. We demonstrated that YC-1 also inhibited hypoxia-induced activation of nuclear factor (NF)-kappaB, a downstream target of Akt. Two modulators of the Akt/NF-kappaB pathway, caffeic acid phenethyl ester and evodiamine, were observed to decrease HIF-1alpha expression. Additionally, overexpression of NF-kappaB partly reversed the ability of wortmannin to inhibit HIF-1alpha-dependent transcriptional activity, suggesting that NF-kappaB contributes to Akt-mediated HIF-1alpha accumulation during hypoxia. Overall, we identify a potential molecular mechanism whereby YC-1 serves to reduce HIF-1 expression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
Blotting, Western
Cell Hypoxia / physiology
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Gene Expression Regulation, Neoplastic / drug effects
Guanylate Cyclase / antagonists & inhibitors
Humans
Hypoxia-Inducible Factor 1 / genetics
Hypoxia-Inducible Factor 1 / metabolism*
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
I-kappa B Kinase / metabolism
Indazoles / pharmacology*
Male
Mitogens / pharmacology
NF-kappa B / metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation / drug effects
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Protein Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects*
Signal Transduction / physiology
TOR Serine-Threonine Kinases

Substances

Enzyme Inhibitors
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Indazoles
Mitogens
NF-kappa B
RNA, Messenger
Aryl Hydrocarbon Receptor Nuclear Translocator
3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
Protein Kinases
MTOR protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
I-kappa B Kinase
Guanylate Cyclase