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B7-H4 downregulation induces mitochondrial dysfunction and enhances doxorubicin sensitivity via the cAMP/CREB/PGC1-α signaling pathway in HeLa cells

  • Signaling and cell physiology
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Abstract

B7-H4 is a B7 family coregulatory protein that inhibits T cell-mediated immunity. B7-H4 is overexpressed in various cancers; however, the functional role of B7-H4 in cancer metabolism is poorly understood. Because mitochondria play pivotal roles in development, proliferation, and death of cancer cells, we investigated molecular and functional alterations of mitochondria in B7-H4-depleted HeLa cells. In a human study, overexpression of B7-H4 was confirmed in the cervices of adenocarcinoma patients (n = 3) compared to noncancer patients (n = 3). In the cell line model, B7-H4 depletion was performed by transfection with small interfering RNA (siRNA). B7-H4 depletion suppressed oxygen consumption rate, ATP production, and mitochondrial membrane potential and mass and increased reactive oxygen species production. In particular, electron transport complex III activity was significantly impaired in siB7-H4-treated cells. Coincidently, depletion of B7-H4 suppressed major mitochondrial regulators (peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PGC1-α] and mitochondrial transcription factor A), a component of oxidative phosphorylation (ubiquinol-cytochrome c reductase core protein 1), and an antiapoptosis protein (Bcl-XL). Mitochondrial dysfunction in siRNA-treated cells significantly augmented oxidative stress, which strongly activated the JNK/P38/caspase axis in the presence of doxorubicin, resulting in increased apoptotic cell death. Investigating the mechanism of B7-H4-mediated mitochondrial modulation, we found that B7-H4 depletion significantly downregulated the cAMP/cAMP response element-binding protein/PGC1-α signaling pathway. Based on these findings, we conclude that B7-H4 has a role in the regulation of mitochondrial function, which is closely related to cancer cell physiology and drug sensitivity.

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF), and funding was granted by the Ministry of Science, ICT & Future Planning of Korea (R13-2007-023-00000-0, 2011-0028925 and 2012R1A2A1A03007595) and by the Ministry of Education of Korea (2010-0020224).

Ethical standards

All experimental procedures were reviewed and approved by the Institutional Review Board of Busan Paik Hospital.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Department of Health Sciences and Technology, Cardiovascular and Metabolic Disease Center, Inje University, Busan, South Korea

    Hyoung Kyu Kim, In-Sung Song, Sun Young Lee, Seung Hun Jeong, Sung Ryul Lee, Hye Jin Heo, Vu Thi Thu, Nari Kim, Kyung Soo Ko, Byoung Doo Rhee & Jin Han

  2. Department of Obstetrics and Gynecology, Busan Paik Hospital, Inje University, Busan, South Korea

    Dae Hun Jeong & Young Nam Kim

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  1. Hyoung Kyu Kim
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Correspondence to Jin Han.

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Kim, H.K., Song, IS., Lee, S.Y. et al. B7-H4 downregulation induces mitochondrial dysfunction and enhances doxorubicin sensitivity via the cAMP/CREB/PGC1-α signaling pathway in HeLa cells. Pflugers Arch - Eur J Physiol 466, 2323–2338 (2014). https://doi.org/10.1007/s00424-014-1493-3

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