Abstract :
[en] Rho GTPases are highly conserved members of the Ras superfamily. They are best known to organize the actin and microtubule cytoskeleton and, thereby, to define cell shape and migration, among other characteristics. Their activity is regulated by several activators and inhibitors. To date, only three human Rho guanine dissociation inhibitors (GDIs) have been identified: RhoGDI1, RhoGDI2, and RhoGDI3. Initially, RhoGDI2 was thought to be specific to immune cells, but it has since been found in various other cell types and tissues, including cancer cells. RhoGDI1 and RhoGDI2 are implicated in multiple human cancers, making them attractive targets for cancer research. While RhoGDI1 has been studied extensively, much less is known about the physiological function(s) of RhoGDI2.
Despite sharing a high structural similarity with RhoGDI1, RhoGDI2 is able to display several specific functions. It has been suggested that its roles probably extend beyond the passive maintenance of RhoGTPases and it was described to have both pro- and anti- tumor properties depending on cancer type and stage.
Our goal was to understand the dual role of RhoGDI2 in cancer, and to elucidate the differences between RhoGDI1 and RhoGDI2.
By immunoprecipitation followed by Mass Spec analysis, we observed that RhoGDI2 potentially interacts with many centrosomal and dynein proteins. Using osteosarcoma cancer cells as experimental models, we then demonstrated that siRNA-mediated suppression of RhoGDI2 expression significantly reduced cell proliferation, an effect that was not observed when RhoGDI1 was silenced. Searching for the underlying mechanisms, we found that RhoGDI2 silencing promoted mitotic errors and centrosomal abnormalities. It also induced supernumerary centrosomes and chromosome congression defects while inhibiting ciliogenesis. As Rho GTPases are also implicated in ciliary defects, we checked the implication of some key Rho GTPases in the modifications observed in RhoGDI2-silenced cells. We showed that silencing of RhoGDI2 promoted the activity of RhoA, but not that of Rac1 or Cdc42, and that the silencing of RhoA rescued the ciliary defects observed upon RhoGDI2 silencing. Furthermore, knocking down RhoGDI2 in NK-92 natural killer cells significantly reduced their tumor-killing abilities, suggesting a critical role in immune synapse formation.
Taken together, these findings point to a previously unrecognized function of RhoGDI2 in centrosomal organization and immune cell activity, positioning RhoGDI2 as both a regulator of cancer cell proliferation and anti-tumor immunity. This multifunctional involvement in cellular processes highlights RhoGDI2 as a compelling target for advancing our understanding of cancer biology and developing more precise therapies.
