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The effects of humanin and its analogues on male germ cell apoptosis induced by chemotherapeutic drugs

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Abstract

Human (HN) prevents stress-induced apoptosis in many cells/tissues. In this study we showed that HN ameliorated chemotherapy [cyclophosphamide (CP) and Doxorubicin (DOX)]-induced male germ cell apoptosis both ex vivo in seminiferous tubule cultures and in vivo in the testis. HN acts by several putative mechanisms via binding to: an IL-12 like trimeric membrane receptor; BAX; or insulin-like growth factor binding protein-3 (IGFBP-3, a proapoptotic factor). To understand the mechanisms of HN on male germ cell apoptosis, we studied five HN analogues including: HNG (HN-S14G, a potent agonist), HNG-F6A (no binding to IGFBP-3), HN-S7A (no self-dimerization), HN-C8P (no binding to BAX), and HN-L12A (a HN antagonist) on CP-induced male germ cell apoptosis in mice. CP-induced germ cell apoptosis was inhibited by HN, HNG, HNG-F6A, HN-S7A, and HN-C8P (less effective); but not by HN-L12A. HN-L12A, but not HN-S7A or HN-C8P, blocked the protective effect of HN against CP-induced male germ cell apoptosis. HN, HN-S7A, and HN-C8P restored CP-suppressed STAT3 phosphorylation. These results suggest that HN: (1) decreases DOX (ex vivo) and CP (in vivo) induced male germ cell apoptosis; (2) action is mediated by the membrane receptor/STAT3 with minor contribution by BAX-binding pathway; (3) self-dimerization or binding to IGFBP-3 may not be involved in HN’s effect in testis. HN is an important molecule in the regulation of germ cell homeostasis after injury and agonistic analogues may be developed for treating male infertility or protection against chemotherapy side effects.

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Acknowledgments

This study supported by the Endocrinology, Metabolism and Nutrition training Grant (T32 DK007571) and UCLA Clinical and Translational Science Institute (UL1TR000124) at Los Angeles Biomedical Research Institute and Harbor-UCLA Medical Center and Grants to P.C. (1R01AG034430, 1R01GM090311, P01AG034906 and 1R01ES020812). We thank Vince Atienza for technical assistance.

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The authors disclose no potential conflicts of interest.

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Authors and Affiliations

  1. Division of Endocrinology, Department of Medicine, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA

    Yue Jia, Aikoui Ohanyan, Yan-He Lue, Ronald S. Swerdloff, Peter Y. Liu & Christina Wang

  2. USC Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA

    Pinchas Cohen

  3. Clinical and Translational Science Center, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1000 West Carson Street, Box 16, Torrance, CA, 90509-2910, USA

    Christina Wang

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  1. Yue Jia
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Correspondence to Christina Wang.

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Jia, Y., Ohanyan, A., Lue, YH. et al. The effects of humanin and its analogues on male germ cell apoptosis induced by chemotherapeutic drugs. Apoptosis 20, 551–561 (2015). https://doi.org/10.1007/s10495-015-1105-5

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