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.

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
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • I-kappa B Kinase
  • Guanylate Cyclase