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The anti-mitotic drug griseofulvin induces apoptosis of human germ cell tumor cells through a connexin 43-dependent molecular mechanism

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Abstract

Griseofulvin, a widely used antifungal antimitotic drug has been proposed as an anti-tumoral treatment by way of in vitro experiments. Recently, in vivo demonstration of griseofulvin efficacy against multiple myeloma in mice argues for its potential as therapeutics for cancer. Nevertheless, the molecular mechanisms by which griseofulvin disrupts cancerous cell progression are far from being understood. In the present study, we found that griseofulvin inhibits human germ cell tumor cell growth through activation of mitochondrial caspase pathway (caspase 9 and 3) leading to the activation of apoptosis rather than an alteration of cell proliferation. Strikingly, we demonstrated that griseofulvin triggered the expression level of connexin 43 (mRNA and protein), a well described tumor-suppressor gene, known to participate in apoptosis regulation. Consistently, together with microtubule instability, a mechanism classically associated with cell death in response to griseofulvin, we observed a disruption of connexin 43/tubulin association concomitant of an enhanced translocation of connexin 43, or an immunoreactive fragment of the protein, from the cytoplasm to the nucleus. Finally, by using siRNA approaches we demonstrated the requirement of connexin 43 in the apoptotic induction of griseofulvin on our tumor cell model. Altogether, these results described a new molecular mechanism connexin 43-dependent targeted by griseofulvin leading to apoptosis of human germ cell tumor cells.

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Acknowledgments

This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM). The authors would like to thank Laure Gilleron for critically reading the manuscript and Jeannine Colombani for secretarial assistance. We thank Dr D. Volle (INSERM U1103, CNRS UMR 6293, and University of Clermont) for critical advice. DC was a fellowship from ANR (05-PCOD-006-02) and ARC and JG is a doctoral and postdoctoral research fellow of the French Ministry of Research and Technology and of EMBO.

Conflict of interest

The authors disclose no potential conflicts of interest.

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Authors and Affiliations

  1. INSERM U 1065, Centre Méditerranéen de Médecine Moléculaire, 06204, Nice Cedex 3, France

    V. Mauro, D. Carette, R. Pontier-Bres, D. Czerucka, J. Gilleron & G. Pointis

  2. University of Nice Sophia Antipolis, 151 Route Saint Antoine de Ginestière, BP 2 3194, 06204, Nice Cedex 3, France

    V. Mauro, D. Carette, R. Pontier-Bres, D. Czerucka & G. Pointis

  3. UMR S775, University Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France

    J. Dompierre, D. Segretain & J. Gilleron

  4. University Versailles Saint Quentin, Versailles, France

    D. Segretain

  5. INSERM U1065, Bâtiment Universitaire Archimed, C3 M, 151 Route Saint Antoine de Ginestière, BP 2 3194, 06204, Nice cedex 3, France

    G. Pointis

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  1. V. Mauro
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  2. D. Carette
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Correspondence to G. Pointis.

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V. Mauro, D. Carette contributed equally to this work.

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Mauro, V., Carette, D., Pontier-Bres, R. et al. The anti-mitotic drug griseofulvin induces apoptosis of human germ cell tumor cells through a connexin 43-dependent molecular mechanism. Apoptosis 18, 480–491 (2013). https://doi.org/10.1007/s10495-012-0800-8

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