P-REX1-Independent, Calcium-Dependent RAC1 Hyperactivation in Prostate Cancer

Abstract

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.

The metastatic promoter DEPDC1B induces epithelial‐mesenchymal transition and promotes prostate cancer cell proliferation via Rac1‐PAK1 signaling

“…Recent research showed that P-REX1 and Vav3 were served as the regulator of Rac1 in modulating the mobility of PCa. 9,10 In addition, RhoH, a regulator of Rac1, which depleted, is able to reduce lamellipodium extension by regulating the localization of Rac1. 11 However, Rho signaling network is complex, and the detail mechanism of Rac1 in mPCa remains largely unknown.…”

“…Dysregulation of the Rac1 signaling pathway, resulting in elevated motile and invasive potential, has been reported in PCa. Recent research showed that P‐REX1 and Vav3 were served as the regulator of Rac1 in modulating the mobility of PCa 9,10 . In addition, RhoH, a regulator of Rac1, which depleted, is able to reduce lamellipodium extension by regulating the localization of Rac1 11 .…”

Evaluation of active Rac1 levels in cancer cells: A case of misleading conclusions from immunofluorescence analysis

“…To test this hypothesis, we first used prostate cancer cell lines with different levels of basal Rac1-GTP. We have previously shown that androgen-independent aggressive cell lines DU145, PC3, and PC3-ML have high levels of basal active Rac1 when compared with a normal prostate epithelial cell line (RWPE1), prostate hyperplasic cell line (BPH-1), and less aggressive prostate cancer cell lines (LNCaP and LNCaP variants), which all have low levels of Rac1-GTP (56) (Fig. 6A).…”

“…The extensive interest of our laboratory in the role of Rac1 signaling in tumorigenesis and metastasis (3,56,57) prompted us to use the anti-Rac1-GTP antibody in a number of cancer cell models. In the course of these studies, we stumbled upon a number of inconsistencies that persuaded us to pursue a deeper characterization of this antibody.…”

Phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1 is a diagnostic and prognostic biomarker for hepatocellular carcinoma

“…In this study, we identified that P-Rex1 was overexpressed in liver tumor tissues (Figures 1 and 4 ), which was consistent with previous reports in other cancers. Baker et al[ 33 ] reported hyperactivation of P-Rex1 in prostate cancer[ 33 ]. P-Rex1 amplification is also involved in the progression of melanoma via the PAK1/P38 pathways[ 34 ].…”