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ABCB7 simultaneously regulates apoptotic and non-apoptotic cell death by modulating mitochondrial ROS and HIF1α-driven NFκB signaling

Oncogene volume 39, pages 1969–1982 (2020)Cite this article

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Abstract

Most of the mechanisms governing apoptotic and non-apoptotic cell death are regulated independently. However, cells may experience various stresses that lead to both apoptotic and non-apoptotic cell death. In particular, cancer cells require a program that simultaneously avoids these forms of cell death, but the mechanism by which they are able to do so is currently unclear. Here, we show that ABC transporter subfamily B member 7 (ABCB7), one of the mitochondrial iron transporters, induces the hypoxia-independent accumulation of hypoxia-inducible factor 1 alpha by controlling intracellular iron homeostasis and inhibits both apoptotic and non-apoptotic cell death. Mechanistically, ABCB7 mitigates non-apoptotic cell death by reducing levels of mitochondrial reactive oxygen species. ABCB7 also suppresses apoptosis by inhibiting the expression of leucine zipper downregulated in cancer 1, an inhibitor of nuclear factor-kappa B signaling. Therefore, our results support that ABCB7 is crucial in controlling both apoptotic and non-apoptotic cell death and indicate that the fine-tuning of intracellular iron homeostasis may be a novel anticancer strategy.

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Acknowledgements

The authors thank the members of the Cancer Growth Regulation Laboratory for their discussions and technical assistance. This work was supported by grants to Hyunggee Kim from the National Research Foundation (NRF) [grant numbers 2015R1A5A1009024, 2017R1E1A1A01074205 and 2017M3A9A8031425], and the School of Life Sciences and Biotechnology for BK21 Plus, Korea University.

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Authors and Affiliations

  1. Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea

    Jung Yun Kim, Jun-Kyum Kim & Hyunggee Kim

  2. Institute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea

    Jung Yun Kim, Jun-Kyum Kim & Hyunggee Kim

  3. Department of Medical Engineering, Korea University College of Medicine, Seoul, 02841, Republic of Korea

    Hyunggee Kim

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  1. Jung Yun Kim
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HK, JYK, and JKK designed the research experiments. JYK performed all experiments and analyzed the data. JYK contributed new analytical tools. HK and JYK wrote the manuscript.

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Correspondence to Hyunggee Kim.

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Kim, J.Y., Kim, JK. & Kim, H. ABCB7 simultaneously regulates apoptotic and non-apoptotic cell death by modulating mitochondrial ROS and HIF1α-driven NFκB signaling. Oncogene 39, 1969–1982 (2020). https://doi.org/10.1038/s41388-019-1118-6

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