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

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