1. ¹Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan
2. ²School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
3. ³Yung-Shin Pharmaceutical Industry Co. Ltd., China Medical College, Taichung, Taiwan
4. ⁴Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung, Taiwan

Correspondence: Professor CM Teng, Pharmacological Institute, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Sect. 1, Taipei 100, Taiwan. E-mail: cmteng@ntumc.org

Received 3 April 2006; Revised 19 October 2006; Accepted 25 October 2006; Published online 8 January 2007.

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