[en] Background
Rho GTPases of the Ras subfamily (RhoA, Rac1, Cdc42 ….) are potent regulators of multiple biological processes and their role in cancer is well documented. Amongst their many regulators, RhoGDI1 and RhoGDI2 share many functions but also have specific roles. RhoGDI2 was initially identified in hematopoietic cells where it localizes in the cytoplasm and has roles in cytoskeleton organization and cell survival. It was later found to be differentially expressed in other cell types, including several human cancers where its expression has been correlated to either good or bad prognosis.
Aim
This study aims to enhance our understanding of the underlying mechanisms contributing to the dual role of RhoGDI2 in cancer.
Methods
To identify the mechanistic functions of RhoGDI2, human osteosarcoma U-2 OS and MG-63 cells are used as exploratory models to observe modifications in cell cycle progression upon RhoGDI2 silencing, as compared to RhoGDI1 silencing. We also exploit human natural killer (NK-92) cells to investigate RhoGDI2’s role in cancer cells control by the innate immune system.
Results
• RhoGDI2 suppression in cancer cells significantly reduces their proliferation rate, as compared to RhoGDI1 suppression.
• Through MS studies, CEP192, a centrosomal protein playing key role in mitosis, was identified as a potential interactor of RhoGDI2.
• RhoGDI2 silencing affects the centrosome-primary cilium complex, an organelle with multiple cell regulatory functions, including cell division and transduction of extracellular signals, as compared to RhoGDI1 silencing.
• Preliminary experiments showed that co-silencing of Rac1, a key Rho GTPase, with RhoGDI2 rescued this loss-of-phenotype in MG-63 cells. RhoA downregulation did not seem to have any influence.
• Knocking down RhoGDI2 in NK-92 significantly reduced their tumor killing ability.
Conclusion
Altogether our data gives insight into the reasons why RhoGDI2 could be considered both as “pro-tumor” by stimulating cancer cell proliferation, but also as “anti-tumor” by participating in cancer cell killing by immune cells.
