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Cisplatin-induced primordial follicle oocyte killing and loss of fertility are not prevented by imatinib

Nature Medicine volume 18, pages 1170–1172 (2012)Cite this article

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To the Editor:

TAp63α is the predominant member of the Trp53 family (consisting of the tumor suppressors Trp53, Trp63 and Trp73), expressed in primordial follicle oocytes1 and is essential for oocyte death after genotoxic stress2. How DNA damage leads to the activation of TAp63α is poorly defined. Gonfloni et al.3 reported that inhibition of c-Abl with imatinib (Gleevec), which was designed to inhibit the oncogenic kinase BCR-ABL, protects oocytes from cisplatin-induced killing in mice, and therefore they proposed that c-Abl is crucial for the induction of TAp63-mediated apoptosis. However, the relationships between c-ABL, TAp63 and DNA damage–induced cell death are complex4,5, and imatinib itself is actually known to promote apoptosis by inhibiting certain kinases that promote cell survival, such as the stem cell factor receptor, c-Kit6,7. Accordingly, imatinib is used clinically for the treatment of not only BCR-ABL+ chronic myelogenous leukemia but also c-Kit–mutated gastrointestinal stromal tumors8. Of particular concern, c-Kit is crucial for oocyte survival, with blocking antibodies to c-Kit causing follicular atresia9. We therefore independently explored the impact of imatinib on the response of oocytes to DNA damage induced by cisplatin. We found that imatinib did not protect primordial follicle oocytes from cisplatin-induced apoptosis or prevent loss of fertility in two independent strains of mice.

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Figure 1: Pretreatment with imatinib does not protect primordial follicle oocytes from DNA damage–induced death or rescue cisplatin-induced loss of fertility in CD1 mice.

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Acknowledgements

This work was supported by fellowships and grants from the National Health and Medical Research Council (NHMRC Australia; program grants 494802 and 257502, fellowships to J.K.F. (441101), K.J.H. (494836), C.L.S. (406675), A.S. (461299) and T.P.S. (575503)); the Leukemia and Lymphoma Society (Specialised Centre of Research grant 7015), the US National Cancer Institute (CA 80188 and CA 43540) and the Victorian Cancer Council Fellowship to C.L.S. (CRF10_20). We thank M. Olshansky for help with calculations. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme.

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Author notes

  1. Jeffrey B Kerr, Karla J Hutt, Andreas Strasser, Jock K Findlay and Clare L Scott: These authors contributed equally to this work.

Authors and Affiliations

  1. Monash University, Clayton, Victoria, Australia

    Jeffrey B Kerr

  2. Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia

    Karla J Hutt & Jock K Findlay

  3. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Michele Cook, Terence P Speed, Andreas Strasser & Clare L Scott

  4. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

    Terence P Speed, Andreas Strasser & Clare L Scott

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  1. Jeffrey B Kerr
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Contributions

J.B.K. and K.J.H. performed and planned experiments, interpreted data and wrote the manuscript. M.C. helped with experiments and contributed data. T.P.S. performed statistical analysis and contributed to manuscript writing. A.S., J.K.F. and C.L.S. conceived of the study, planned experiments, interpreted data and wrote the manuscript.

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Correspondence to Clare L Scott.

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Supplementary Methods, Supplementary Tables 1–6 and Supplementary Figures 1–6 (PDF 7621 kb)

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Kerr, J., Hutt, K., Cook, M. et al. Cisplatin-induced primordial follicle oocyte killing and loss of fertility are not prevented by imatinib. Nat Med 18, 1170–1172 (2012). https://doi.org/10.1038/nm.2889

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