Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis.
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 the upregulation of P-Rex1, a Rac-selective GEF synergistically activated by Gbetagamma 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 cells, such as CWR22Rv1, increased cell migration and invasion through Rac-dependent lamellipodia formation. More importantly, using a mouse xenograft model, we showed that the 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.
Qin
J
J
Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA.
Xie
Y
Y
Wang
B
B
Hoshino
M
M
Wolff
D W
DW
Zhao
J
J
Scofield
M A
MA
Dowd
F J
FJ
Lin
M-F
MF
Tu
Y
Y
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000502:physiology; D015854:Up-Regulation; D020744:rac GTP-Binding Proteins / Q000378:metabolism
C527276:CXCR4 protein, human; D020662:Guanine Nucleotide Exchange Factors; C453280:PREX1 protein, human; D019718:Receptors, CXCR4; D066246:ErbB Receptors; D020744:rac GTP-Binding Proteins