, Volume 20, Issue 4, pp 551–561 | Cite as

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

  • Yue Jia
  • Aikoui Ohanyan
  • Yan-He Lue
  • Ronald S. Swerdloff
  • Peter Y. Liu
  • Pinchas Cohen
  • Christina WangEmail author
Original Paper


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.


Humanin Testis Germ cell apoptosis Chemotherapy 



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.

Conflict of interest

The authors disclose no potential conflicts of interest.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yue Jia
    • 1
  • Aikoui Ohanyan
    • 1
  • Yan-He Lue
    • 1
  • Ronald S. Swerdloff
    • 1
  • Peter Y. Liu
    • 1
  • Pinchas Cohen
    • 2
  • Christina Wang
    • 1
    • 3
    Email author
  1. 1.Division of Endocrinology, Department of MedicineLos Angeles Biomedical Research Institute, Harbor-UCLA Medical CenterTorranceUSA
  2. 2.USC Leonard Davis School of GerontologyUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.Clinical and Translational Science CenterLos Angeles Biomedical Research Institute, Harbor-UCLA Medical CenterTorranceUSA

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