Deciphering the dual functions of RhoGDI2 in Cancer Biology

RhoGDI2 is a RhoGTPase regulator that was initially identified in hematopoietic cells where it localizes in the cytoplasm and has roles in cytoskeleton organization and cell survival, amongst others. It was later found to be differentially expressed in other cell types and tissues, including several human cancers where its expression has been correlated to either good or bad prognosis. In order to identify the underlying mechanisms, we knocked down its expression in cancer cell lines (PC-3,prostatic adenocarcinoma; U-2 OS, osteosarcoma) and evaluated the resulting phenotype. We observed that repression of RhoGDI2 expression in cancer cells significantly reduces their proliferation rate. Such effect was not observed when the closely related RhoGDI1 was silenced, underlining the relevance of our findings. Searching for mechanisms explaining such effect, we found that RhoGDI2 silencing affects also the centrosome-primary cilium complex, an organelle with multiple cell regulatory functions, including reception and transduction of extracellular signals. Considering its abundance in immune cells and the striking similarities between primary cilia and immune synapses, we next verified if RhoGDI2 could play a role in the control of cancer cells by the innate immune system. In preliminary experiments we have shown that knocking down RhoGDI2 in NK-92 (natural killer cells) significantly reduces their tumor killing abilities. Altogether our data would explain why RhoGDI2 could be considered both as “protumor” by stimulating cancer cell proliferation, but also as “anti-tumor” by participating in cancer cell killing by immune cells.