YC-1 inhibits HIF-1 expression in prostate cancer cells: Contribution of Akt/NF-κB signaling to HIF-1α 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

Research output: Contribution to journalArticle

132 Citations (Scopus)

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-1α and HIF-1β accumulation in response to hypoxia or mitogen treatment in PC-3 prostate cancer cells. Neither HIF-1α 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-1α expression at the translational step. We demonstrated that YC-1 also inhibited hypoxia-induced activation of nuclear factor (NF)-κB, a downstream target of Akt. Two modulators of the Akt/NF-κB pathway, caffeic acid phenethyl ester and evodiamine, were observed to decrease HIF-1α expression. Additionally, overexpression of NF-κB partly reversed the ability of wortmannin to inhibit HIF-1α-dependent transcriptional activity, suggesting that NF-κB contributes to Akt-mediated HIF-1α accumulation during hypoxia. Overall, we identify a potential molecular mechanism whereby YC-1 serves to reduce HIF-1 expression.

Original languageEnglish
Pages (from-to)3941-3951
Number of pages11
JournalOncogene
Volume26
Issue number27
DOIs
Publication statusPublished - Jun 7 2007
Externally publishedYes

Keywords

  • Akt
  • HIF-1
  • NF-κB
  • Prostate cancer
  • YC-1

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Sun, H. L., Liu, Y. N., Huang, Y. T., Pan, S. L., Huang, D. Y., Guh, J. H., Lee, F. Y., Kuo, S. C., & Teng, C. M. (2007). YC-1 inhibits HIF-1 expression in prostate cancer cells: Contribution of Akt/NF-κB signaling to HIF-1α accumulation during hypoxia. Oncogene, 26(27), 3941-3951. https://doi.org/10.1038/sj.onc.1210169