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Apoptosis (2015) 20:551561 DOI 10.1007/s10495-015-1105-5
ORIGINAL PAPER
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 Wang
Published online: 10 February 2015 Springer Science+Business Media New York 2015
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 ve HN analogues including: HNG (HN-S14G, a potent agonist), HNG-F6A (no binding to IGFBP-3), HNS7A (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, HNS7A, 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 HNs 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.
Keywords Humanin Testis Germ cell apoptosis
Chemotherapy
Introduction
HN is a mitochondrial derived 24 amino acid peptide which prevents cell damage from stress/injury in many tissue/cells, including neuronal tissue [13], heart and blood vessel [4, 5], bone [6], blood-derived cells [7, 8], pancreas [9, 10], and male germ cells [11, 12]. We have previously shown that male germ cell apoptosis can be induced in rodents [13, 14], monkeys [15, 16], and men [17] by a variety of apoptotic stimuli including testicular hyperthermia, and administration of insulin-like growth factor...