phosphatidylinositol-4-phosphate and Neoplasm-Metastasis

This article focuses on the emerging roles for phosphatidylinositol 4-phosphate and the phosphatidylinositol 4-kinases in cancer. Phosphatidylinositol 4-phosphate is a common substrate for both the phosphatidylinositol 3-kinase and phospholipase C pathways, and has been implicated in the membrane targeting of proteins such as Girdin/GIV and OSBP. Alterations to phosphatidylinositol 4-kinase expression levels can modulate MAP kinase and Akt signalling, and are important for chemoresistance, tumour angiogenesis and the suppression of apoptosis and metastases. Recent improvements in high-throughput screening assays, and the discoveries that some anti-viral molecules are isoform selective phosphatidylinositol 4-kinase inhibitors have advanced the drugability of these enzymes.

Topics: 1-Phosphatidylinositol 4-Kinase; Antineoplastic Agents; Apoptosis; Drug Resistance, Neoplasm; High-Throughput Screening Assays; Humans; Membrane Lipids; Microfilament Proteins; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phospholipids; Signal Transduction; Type C Phospholipases; Vesicular Transport Proteins

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 IIIα (PI4KIIIα), and SAC1 phosphatase that dephosphorylates phosphatidylinositol-4-phosphate as potential candidate CXCR4 regulators. CXCR4 interacted with PI4KIIIα membrane targeting machinery recruiting them to the plasma membrane for PI4P production. Consistent with this interaction, PI4KIIIα was found tightly linked to the CXCR4 induced PC cell invasion. Thus, ablation of PI4KIIIα 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 PI4KIIIα expression in metastatic tumors vs. the primary tumor counterparts, further supporting the PI4KIIIα role in tumor metastasis. Furthermore, we also identified an unexpected function of PI4KIIIα in GPCR signaling where CXCR4 regulates PI4KIIIα activity and mediate tumor metastasis. Altogether, our study identifies a novel cross-talk between PI4KIIIα and CXCR4 in promoting tumor metastasis and suggests that PI4KIIIα pharmacological targeting may have therapeutic benefit for advanced prostate cancer patients.

Topics: 1-Phosphatidylinositol 4-Kinase; Adaptor Proteins, Signal Transducing; Cell Division; Cell Line, Tumor; Chemokines; Humans; Male; Membrane Microdomains; Membrane Proteins; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Phosphatidylinositol Phosphates; Prostatic Neoplasms; Protein Interaction Mapping; Protein Transport; Proteins; Receptors, CXCR4; Receptors, G-Protein-Coupled; Recombinant Fusion Proteins; RNA Interference; RNA, Small Interfering