Elevated P-Rex1 Characterizes Metastatic Melanoma Cells

Cancer researchers have found that the protein P-Rex1(Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1) plays an important role in melanoblast migration and the progression of melanoma to metastasis in mice and humans.

P-Rex1 is a guanine nucleotide-exchange factor for the RHO family of small GTP-binding proteins (RACs). It has been shown to bind to and activate RAC1 by exchanging bound GDP for free GTP. The encoded protein, which is found mainly in the cytoplasm, is activated by phosphatidylinositol-3,4,5-trisphosphate and the beta-gamma subunits of heterotrimeric G proteins. It has been suggested that P-Rex1 is upregulated by the activity of the BRAF gene.

Investigators at the University of North Carolina (Chapel Hill, USA) worked with a line of mice that had been genetically engineered to lack the P-Rex1 gene. These animals demonstrated a melanoblast migration defect during development that was evinced by a white belly. Of tremendous interest was the discovery that mice lacking P-Rex1 were resistant to metastasis when crossed to a mouse model of melanoma.

The findings from the mouse study led the investigators to analyze human melanoma cell lines and tumor tissue. They reported in the November 22, 2011, online edition of the journal Nature Communications that P-Rex1 was elevated in the majority of the melanoma cell cultures and tumor specimens.

“As a physician and scientist, I know firsthand the frustration of having very limited therapeutic options to offer to patients with metastatic melanoma,” said contributing author Dr. Nancy Thomas, professor of dermatology at the University of North Carolina. “Pinpointing that P-Rex1 plays a key role in metastasis gives us a better understanding of how the drug vemurafenib may work and a target for developing new treatments.”

Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (at amino acid position number 600 on the BRAF protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. Melanoma cells without this mutation are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.

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