The
GTPase Rac1 is a well-established master regulator of cell motility and invasiveness contributing to
cancer metastasis. Dysregulation of the Rac1 signaling pathway, resulting in elevated motile and invasive potential, has been reported in multiple
cancers. However, there are limited studies on the regulation of Rac1 in
prostate cancer. Here, we demonstrate that aggressive
androgen-independent
prostate cancer cells display marked hyperactivation of Rac1. This hyperactivation is independent of P-Rex1 activity or its direct activators, the PI3K product PIP3 and Gβγ subunits. Furthermore, we demonstrate that the motility and invasiveness of PC3
prostate cancer cells is independent of P-Rex1, supporting the analysis of publicly available datasets indicating no correlation between high P-Rex1 expression and
cancer progression in patients. Rac1 hyperactivation was not related to the presence of activating Rac1 mutations and was insensitive to overexpression of a Rac-GAP or the silencing of specific Rac-GEFs expressed in
prostate cancer cells. Interestingly, active Rac1 levels in these cells were markedly reduced by elevations in intracellular
calcium or by serum stimulation, suggesting the presence of an alternative means of Rac1 regulation in
prostate cancer that does not involve previously established paradigms.