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NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction

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Abstract

Mitochondrial respiration is required for hypoxia-inducible factor (HIF)-1α stabilization, which is important for tumor cell survival, proliferation, and angiogenesis. Herein, small molecules that inhibit HIF-1α protein stability by targeting mitochondrial energy production were screened using the Library of Pharmacologically Active Compounds and cell growth assay in galactose or glucose medium. NNC 55-0396, a T-type Ca2+ channel inhibitor, was selected as a hit from among 1,280 small molecules. NNC 55-0396 suppressed mitochondrial reactive oxygen species-mediated HIF-1α expression as well as stabilization by inhibiting protein synthesis in a dose-dependent manner. NNC 55-0396 inhibited tumor-induced angiogenesis in vitro and in vivo by suppressing HIF-1α stability. Moreover, NNC 55-0396 significantly suppressed glioblastoma tumor growth in a xenograft model. Thus, NNC 55-0396, a small molecule targeting T-type Ca2+ channel, was identified by the systemic cell-based assay and was shown to have antiangiogenic activity via the suppression of HIF-1α signal transduction. These results provide new insights into the biological network between ion channel and HIF-1α signal transduction.

Key message

  • HIF-1α overexpression has been demonstrated in hypoxic cancer cells.

  • NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibited HIF-1α expression via both proteasomal degradation and protein synthesis pathways.

  • T-type Ca2+ channel inhibitors block angiogenesis by suppressing HIF-1α stability and synthesis.

  • NNC 55-0396 could be a potential therapeutic drug candidate for cancer treatment.

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Acknowledgments

This study was partly supported by grants from the National Research Foundation of Korea funded by the Korean government (MSIP; 2010-0017984, 2012M3A9D1054520), the Translational Research Center for Protein Function Control, KRF (2009-0083522), the Next-Generation BioGreen 21 Program (No. PJ0079772012), Rural Development Administration, National R&D Program, Ministry of Health &Welfare (0620360-1), and the Brain Korea 21 Plus Project, Republic of Korea.

Conflict of interest

There is no conflict of interest to disclose.

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Authors and Affiliations

  1. Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, South Korea

    Ki Hyun Kim, Dongyoung Kim, Ju Yeol Park, Yong-Hee Cho, Kang-Yell Choi & Ho Jeong Kwon

  2. Department of Pharmaceutical Engineering, University of Sun Moon, Chungnam, 330-150, South Korea

    Hye Jin Jung

  3. Department of Physiology, Cardiovascular and Metabolic Disease Center, Inje University, Busan, 614-749, South Korea

    Hyoung Kyu Kim & Jin Han

  4. Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, 120-752, South Korea

    Ho Jeong Kwon

  5. Chemical Genomics National Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, South Korea

    Ho Jeong Kwon

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  1. Ki Hyun Kim
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Correspondence to Ho Jeong Kwon.

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Kim, K.H., Kim, D., Park, J.Y. et al. NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction. J Mol Med 93, 499–509 (2015). https://doi.org/10.1007/s00109-014-1235-1

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  • DOI: https://doi.org/10.1007/s00109-014-1235-1

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