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Insulin-Like Growth Factor-I Is an Important Antiapoptotic Factor for Rat Leydig Cells during Postnatal Development

Department of Woman and Child Health (E.C., F.Z., C.C.-S., K.V.S., O.S.), Paediatric Endocrinology Unit, Astrid Lindgren Children’s Hospital, and Departments of Clinical Chemistry (M.A.) and Oncology and Pathology (O.L.), Division of Cellular and Molecular Tumor Pathology, Karolinska Institute and University Hospital, SE 17176 Stockholm, Sweden

Address all correspondence and requests for reprints to: Eugenia Colón, Department of Woman and Child Health, Paediatric Endocrinology Unit, Astrid Lindgren Children’s Hospital, Karolinska Institute and University Hospital, SE 17176 Stockholm, Sweden. E-mail: eugenia.colon{at}ki.se.

The present investigation examines the influence of IGF-I and the role of IGF-I receptor (IGF-IR) in the apoptosis/survival of Leydig cells. Immunohistochemical analysis of the rat testis at different ages revealed that the level of the phosphorylated IGF-IR increases from birth to d 20 of postnatal life, remaining high in the adult testis. Western blotting revealed that this level is higher in Leydig cells isolated from 40-d-old than from 10- or 60-d-old rats. Application of the terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay revealed that IGF-I decreases the level of apoptosis in Leydig cells at all stages of development, and the selective inhibitor of IGF-IR, picropodophyllin, blocks this antiapoptotic effect. The mechanism underlying the antiapoptotic action of IGF-I involves the phosphatidylinositol 3-kinase/Akt pathway, and in immature Leydig cells, this growth factor enhances the expression of Bcl-2 and cellular inhibitor of apoptosis proteins 2, while preventing activation of caspase-3 by cleavage. Furthermore, IGF-II and high concentrations of insulin also evoke phosphorylation of IGF-IR and, like IGF-I, enhance the expression of the steroidogenic acute regulatory protein by Leydig cells. Inhibition of IGF-IR by picropodophyllin decreases the survival of Leydig cells, both in the presence and absence of IGF-I, demonstrating that signaling via the IGF-IR plays an important role in Leydig cell survival.

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