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Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer

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Abstract

Tumor hypoxia is considered the best validated target in clinical oncology because of its significant contribution to chemotherapy failure and drug resistance. As an approach to target hypoxia, we assessed the potential of quercetin, a flavonoid widely distributed in plants, as a anticancer agent under hypoxic conditions and examined its pharmacological mechanisms by primarily focusing on the role of AMP-activated protein kinase (AMPK). Quercetin significantly attenuated tumor growth in an HCT116 cancer xenograft in vivo model with a substantial reduction of AMPK activity. In a cell culture system, quercetin more dramatically induced apoptosis of HCT116 cancer cells under hypoxic conditions than normoxic conditions, and this was tightly associated with inhibition of hypoxia-induced AMPK activity. An in vitro kinase assay demonstrated that quercetin directly inhibits AMPK activity. Inhibition of AMPK by expressing a dominant-negative form resulted in an increase of apoptosis under hypoxia, and a constitutively active form of AMPK effectively blocked quercetin-induced apoptosis under hypoxia. Collectively, our data suggest that quercetin directly inhibits hypoxia-induced AMPK, which plays a protective role against hypoxia. Quercetin also reduced the activity of hypoxia-inducible factor-1 (HIF-1), a major transcription factor for adaptive cellular response to hypoxia. Moreover, quercetin sensitized HCT116 cancer cells to the anticancer drugs cisplatin and etoposide under hypoxic conditions. Our findings suggest that AMPK may serve as a novel target for overcoming tumor hypoxia-associated negative aspects.

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Acknowledgments

This work was supported by a grant from the Kyung Hee University in 2010 (KHU-20100849).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, 130-701, Korea

    Hak-Su Kim, Tirawat Wannatung, Sooho Lee, Woo Kyeom Yang, Wonchae Choe, Insug Kang, Sung-Soo Kim & Joohun Ha

  2. Department of Pharmacology, College of Pharmacy, Kyung Hee University, Seoul, 130-701, Korea

    Sung Hyun Chung

  3. Department of Biological Sciences and the Research Center for Women’s Diseases, Sookmyung Women’s University, Seoul, 140-742, Korea

    Jong-Seok Lim

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  1. Hak-Su Kim
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Correspondence to Joohun Ha.

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Kim, HS., Wannatung, T., Lee, S. et al. Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer. Apoptosis 17, 938–949 (2012). https://doi.org/10.1007/s10495-012-0719-0

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