PI3Kgamma activation by CXCL12 regulates tumor cell adhesion and invasion.
Tumor dissemination is a complex process, in which certain steps resemble those in leukocyte homing. Specific chemokine/chemokine receptor pairs have important roles in both processes. CXCL12/CXCR4 is the most commonly expressed chemokine/chemokine receptor pair in human cancers, in which it regulates cell adhesion, extravasation, metastatic colonization, angiogenesis, and proliferation. All of these processes require activation of signaling pathways that include G proteins, phosphatidylinositol-3 kinase (PI3K), JAK kinases, Rho GTPases, and focal adhesion-associated proteins. We analyzed these pathways in a human melanoma cell line in response to CXCL12 stimulation, and found that PI3Kgamma regulates tumor cell adhesion through mechanisms different from those involved in cell invasion. Our data indicate that, following CXCR4 activation after CXCL12 binding, the invasion and adhesion processes are regulated differently by distinct downstream events in these signaling cascades.
Monterrubio
María
M
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, E-28049 Madrid, Spain.
Mellado
Mario
M
Carrera
Ana C
AC
Rodríguez-Frade
José Miguel
JM
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000096:biosynthesis
C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D007527:Isoenzymes; D019718:Receptors, CXCR4; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; D053612:Janus Kinases; D019204:GTP-Binding Proteins; D020559:Monomeric GTP-Binding Proteins