title: The anti-mitotic drug griseofulvin induces apoptosis of human germ cell tumor cells through a connexin 43-dependent molecular mechanism.
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.
authors: INSERM U 1065, Centre Méditerranéen de Médecine Moléculaire, 06204 Nice Cedex 3, France.
authors: V
authors: V
authors: Mauro
authors: D
authors: D
authors: Carette
authors: R
authors: R
authors: Pontier-Bres
authors: J
authors: J
authors: Dompierre
authors: D
authors: D
authors: Czerucka
authors: D
authors: D
authors: Segretain
authors: J
authors: J
authors: Gilleron
authors: G
authors: G
authors: Pointis
mesh_terms: D050256:Antimitotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000096:biosynthesis; D053453:Caspase 9 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D006118:Griseofulvin / Q000494:pharmacology*; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009373:Neoplasms, Germ Cell and Embryonal / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D014404:Tubulin / Q000378:metabolism
chemical_list: D050256:Antimitotic Agents; D018031:Connexin 43; C500216:GJA1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014404:Tubulin; D006118:Griseofulvin; D053148:Caspase 3; D053453:Caspase 9