A novel cross-talk between CXCR4 and PI4KIIIα in prostate cancer cells

Chemokine signaling regulates cell migration and tumor metastasis. CXCL12, a member of the chemokine family, and its receptor, CXCR4, a G protein coupled receptor (GPCR), are key mediators of prostate-cancer (PC) bone metastasis. In PC cells androgens activate CXCR4 gene expression and receptor signaling on lipid rafts, which induces protease expression and cancer cell invasion. To identify novel lipid-raft-associated CXCR4 regulators supporting invasion/metastasis, we performed a SILAC-based quantitative proteomic analysis of lipid-rafts derived from PC3 stable cell lines with overexpression or knockdown of CXCR4. This analysis identified the evolutionarily conserved phosphatidylinositol 4-kinase III alpha (PI4KIII alpha), and SAC1 phosphatase that dephosphorylates phosphatidylinositol-4-phosphate as potential candidate CXCR4 regulators. CXCR4 interacted with PI4KIII alpha membrane targeting machinery recruiting them to the plasma membrane for PI4P production. Consistent with this interaction, PI4KIII alpha was found tightly linked to the CXCR4 induced PC cell invasion. Thus, ablation of PI4KIII alpha in CXCR4-expressing PC3 cells reduced cellular invasion in response to a variety of chemokines. Immunofluorescence microscopy in CXCR4-expressing cells revealed localized production of PI4P on the invasive projections. Human tumor studies documented increased PI4KIII alpha expression in metastatic tumors vs. the primary tumor counterparts, further supporting the PI4KIIIa role in tumor metastasis. Furthermore, we also identified an unexpected function of PI4KIII alpha in GPCR signaling where CXCR4 regulates PI4KIII alpha activity and mediate tumor metastasis. Altogether, our study identifies a novel cross-talk between PI4KIII alpha and CXCR4 in promoting tumor metastasis and suggests that PI4KIII alpha pharmacological targeting may have therapeutic benefit for advanced prostate cancer patients.