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

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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.

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Acknowledgements

We thank Yu-Chun Huang, Yi-Fan Ma, Paul Yueh-Jen Hsu and Po-Cheng Chiang for valuable discussion of experimental technique. We also thank Shu-Hui Chiang for providing us with critical reagents that made this work possible. This work was supported by a research grant from Yung-Shin Pharmaceutical Industry Co. Ltd. and NSC 94-2320-B002-038 from the National Science Council of the Republic of China, Taiwan.

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Authors and Affiliations

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

    H-L Sun, Y-N Liu, Y-T Huang, S-L Pan, D-Y Huang & C-M Teng

  2. School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan

    J-H Guh

  3. Yung-Shin Pharmaceutical Industry Co. Ltd., China Medical College, Taichung, Taiwan

    F-Y Lee

  4. Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung, Taiwan

    S-C Kuo

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  1. H-L Sun
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Correspondence to C-M Teng.

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Sun, HL., Liu, YN., Huang, YT. et al. YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-κB signaling to HIF-1α accumulation during hypoxia. Oncogene 26, 3941–3951 (2007). https://doi.org/10.1038/sj.onc.1210169

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