Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis

Abstract

Excessive activation of G-protein coupled receptor (GPCR) and receptor tyrosine kinase (RTK) pathways has been linked to prostate cancer metastasis. Rac activation by guanine-nucleotide exchange factors (GEFs) plays an important role in directional cell migration, a critical step of tumor metastasis cascades. We found that upregulation of P-Rex1, a Rac-selective GEF synergistically activated by Gβγ freed during GPCR signaling and PIP3 generated during either RTK or GPCR signaling, strongly correlates with metastatic phenotypes in both prostate cancer cell lines and human prostate cancer specimens. Silencing endogenous P-Rex1 in metastatic prostate cancer PC-3 cells selectively inhibited Rac activity and reduced cell migration and invasion in response to ligands of both epidermal growth factor receptor and G-protein coupled CXC chemokine receptor 4. Conversely, expression of recombinant P-Rex1, but not its “GEF-dead” mutant, in non-metastatic prostate cancer CWR22Rv1 cells increased cell migration and invasion via Rac-dependent lamellipodia formation. More importantly, using a mouse xenograft model, we demonstrated that expression of P-Rex1, but not its mutant, induced lymph node metastasis of CWR22Rv1 cells without an effect on primary tumor growth. Thus, by functioning as a coincidence detector of chemotactic signals from both GPCRs and RTKs, P-Rex1-dependent activation of Rac promotes prostate cancer metastasis.

PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

“…Additionally, PREX1 appears to have a specific role in metastasis. The expression of PREX1, but not a GEF-dead mutant, induces spontaneous metastasis in a xenograft prostate cancer mouse model (24), and PREX1 inactivation in mice reduces metastasis in a melanoma transgenic mouse model (23). PREX2 is also overexpressed in numerous cancer types and is frequently mutated in cancer, with especially high mutation rates in melanoma (25)(26)(27).…”

“…PREX1 is overexpressed in a variety of human cancers, including melanoma and breast, prostate, and colon cancer (17,(23)(24)(25)(26). PREX1 knockdown decreases tumor growth in xenograft mouse models of cancer using breast cancer cell lines (17,18).…”

P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer

“…P-Rex2a levels are increased in some human cancers bearing wild-type phosphatase and tensin homolog and mutated PIK3CA, and provokes activation of the phosphoinositide 3-kinase route (Fine et al, 2009). In addition, increased expression of P-Rex1 in prostate cancer has been described, and its presence has been linked to Rac-mediated metastatic potential of prostate cancer cells (Qin et al, 2009). …”

NMR analysis of G-protein βγ subunit complexes reveals a dynamic Gα-Gβγ subunit interface and multiple protein recognition modes

“…More recently, small molecule inhibitors of Gβγ subunit signaling have been identified that bind to the Gβγ hot spot and inhibit Gβγ protein-protein interactions (16). These have been used in cellular and animal models to further implicate Gβγ signaling as a potential therapeutic target in pain (17), inflammation (18), and cancer (19). Understanding the flexible nature of this surface is important for developing approaches to target Gβγ with "drug-like" molecules for treatment of disease.…”