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Aberrant IDH3α expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis

Oncogene volume 34, pages 4758–4766 (2015)Cite this article

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Abstract

Cancer cells gain a growth advantage through the so-called Warburg effect by shifting glucose metabolism from oxidative phosphorylation to aerobic glycolysis. Hypoxia-inducible factor 1 (HIF-1) has been suggested to function in metabolic reprogramming; however, the underlying mechanism has not been fully elucidated. We found that the aberrant expression of wild-type isocitrate dehydrogenase 3α (IDH3α), a subunit of the IDH3 heterotetramer, decreased α-ketoglutarate levels and increased the stability and transactivation activity of HIF-1α in cancer cells. The silencing of IDH3α significantly delayed tumor growth by suppressing the HIF-1-mediated Warburg effect and angiogenesis. IDH3α expression was associated with the poor postoperative overall survival of lung and breast cancer patients. These results justify the exploitation of IDH3 as a novel target for the diagnosis and treatment of cancers.

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Acknowledgements

We thank Dr M Suematsu, Dr YA Minamishima, and Dr N Hayakawa for critical discussion. This study was supported by the Funding Program for NEXT Generation World-Leading Researchers (NEXT Program) from the Japan Society for the Promotion of Science (JSPS), Japan to HH (No. LS071), by the program for Precursory Research for Embryonic Science and Technology (PRESTO) from Japan Science and Technology Agency (JST) to HH, by the Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to HH, and by Grants-in-Aids for Scientific Research (B) to HH (No. 26293276), for Scientific Research (C) to AM (No. 26461886), for challenging Exploratory Research to HH (No. 26670558) and to MH (No. 26670555), and for Young Scientists (B) to MK (No. 25861088), MY (No. 24791293) and SI (No. 24659563) from MEXT, Japan, by the Sagawa Foundation for the Promotion of Cancer Research to HH, by the Kobayashi Foundation for Cancer Research to HH, by the Takeda Science Foundation to HH, by the Mochida Memorial Foundation for Medical and Pharmaceutical Research to HH, and by the International Science and Technology Cooperation Project of China and Japan to ZL and HH (No. 2010DFA31900).

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Authors and Affiliations

  1. Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, Japan

    L Zeng, A Morinibu, M Kobayashi, Y Zhu, X Wang, Y Goto, T Zhao, K Shinomiya, S Itasaka, M Yoshimura, M Hiraoka & H Harada

  2. Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho,, Kyoto, Japan

    L Zeng, A Morinibu, M Kobayashi, Y Zhu, X Wang, Y Goto, C J Yeom, T Zhao, K Shinomiya & H Harada

  3. Department of Radiation Medicine, Fourth Military Medical University, Shaanxi, China

    L Zeng, X Wang, T Zhao & G Guo

  4. Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Y Zhu

  5. Department of Anesthesia, Kyoto University Hospital, Kyoto University, Kyoto, Japan

    K Hirota

  6. Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK

    E M Hammond

  7. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST),, Kawaguchi, Japan

    H Harada

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  1. L Zeng
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Correspondence to H Harada.

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Zeng, L., Morinibu, A., Kobayashi, M. et al. Aberrant IDH3α expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis. Oncogene 34, 4758–4766 (2015). https://doi.org/10.1038/onc.2014.411

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  • DOI: https://doi.org/10.1038/onc.2014.411

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