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.

Connexin 43 SUMOylation improves gap junction functions between liver cancer stem cells and enhances their sensitivity to HSVtk/GCV

“…In addition to the above-mentioned findings, we observed that Cx43 gene transfection alone partially inhibited tumor growth in mice. This result is consistent with previous reports that considered Cx43 as a tumor suppressor gene (31)(32)(33). However, it is clear that the inhibitory effect of Cx43 alone on tumor growth is extremely limited (31,33).…”

“…This result is consistent with previous reports that considered Cx43 as a tumor suppressor gene (31)(32)(33). However, it is clear that the inhibitory effect of Cx43 alone on tumor growth is extremely limited (31,33). Similarly, the killing effect of HSVtk/GCV alone on liver cancer cells is limited, particularly in CD133 + cell spheres that were cultured in vitro.…”

Gap junction and hemichannel‐independent actions of connexins on cell and tissue functions – An update

“…These results indicate that Cx43 is effective in enhancing the cytotoxicity of DTX by downregulating Bcl-2. Cx43 also aids in the apoptotic effects of germ cell tumors in response to Griseofulvin, an antifungal antimitotic drug, through translocation from the cytoplasm to the nucleus [23]. Cx43 immunoreactive signal was mainly found distributed throughout the cytoplasm of tumoral germ cells and there was no coupling found between adjacent cells.…”

“…In combination with Docetaxel, inhibits cell growth and induces apoptosis Mauro et al [23] JKT-1 cells Cx43…”

“…• Decreases tumor growth [14,15,16,18,19,20,21,22,24,25,32,35,37,38,39] • Delays cell cycle transiƟon [15,20,35,39] • Decreases tumor migraƟon [14,16,18,20,21,34] • Increases apoptosis [22,23,24,25,32] • Reverses EMT [21,34] • Increases tumor migraƟon [18,19,37] examined the effects of Cx43 in mediating the regulation of the actin cytoskeleton of human glioma cells [37]. The authors designed two truncated constructs of Cx43: one lacking the C-terminal tail and one lacking the entire transmembrane domain.…”