Role of SDF-1 (Alpha) CXCR4/MMP in PC Bone Metastasis

摘要

Chemokines and chemokine receptor interactions facilitate the physiological migration of cells. Interaction of chemokines with their receptors leads to the expression/activation of adhesion molecules and proteases. Recent evidence suggests that a cancer cells utilize similar mechanism to metastasize to target tissues for secondary growth. Herein, we hypothesize that SDF-1 (also known as CXCL12) and CXCR4 axis is active in PC cells and CXCL12 and CXCR4 interactions facilitates the metastasis of prostate cancer cells by activating intracellular signaling pathways leading to the expression and release of MMP-9. Using a variety of methods including RT-PCR, ELISA, gelatin zymography, cellular motility and invasion and sub-cellular fractionation of prostate cancer cells, we showed that (a) CXCL12 and CXCR4 axis is active in PC bone metastasis in inducing MMP-9 expression; (b) pharmacological inhibition of PI3 kinase and MAP kinase pathways abrogated the CXCL12 induced invasion of PC-3 cells; (c) CXCL12 induced Akt1 phosphorylation is indispensable for proMMP-9 secretion, migration and invasion of PC-3 cells; (d) CXCR4 over-expression in PC-3 cells induced expression of several members of proteases and chemokines in PC-3 cells and, (e) CXCR4 was localized to lipid raft fractions in PC cells. This data suggests that chemoattractive mechanisms may involve migration of cancer cells towards bone tissue, and that cell signaling induced by binding of the chemokine to its receptor leads to the activation of multiple signaling pathways and subsequent release of MMPs into the local environment.