Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells.

Abstract

BACKGROUND:

The expression level of osteopontin correlates with the metastatic potential of several tumors. Osteopontin is a well-characterized ligand for the alphavbeta3 integrin. The present study was undertaken to elucidate the possible role of osteopontin/alphavbeta3 signaling in prostate cancer cell migration.

RESULTS:

We generated stable prostate cancer cell (PC3) lines that over-express osteopontin (PC3/OPN), mutant OPN in the integrin binding-site (PC3/RGDDeltaRGA), and null for OPN (PC3/SiRNA). The following observations were made in PC3/OPN cells as compared with PC3 cells: 1) an increase in multinucleated giant cells and RANKL expression; 2) an increase in CD44 surface expression, interaction of CD44/MMP-9 on the cell surface, MMP-9 activity in the conditioned medium, and cell migration; 3) western blot analysis of concentrated conditioned medium exhibited equal levels of MMP-9 protein in all PC3 cells. However, zymography analysis demonstrated that the levels of MMP-9 activity in the conditioned media reflect the CD44 surface expression pattern of the PC3 cell lines; 4) although MMP-9 and MMP-2 are secreted by PC3 cells, only the secretion of MMP-9 is regulated by OPN expression. A strong down regulation of the above-mentioned processes was observed in PC3/OPN (RGA) and PC3/SiRNA cells. PC3/OPN cells treated with bisphosphonate (BP) reproduce the down-regulation observed in PC3/OPN (RGA) and PC3/SiRNA cells.

CONCLUSION:

Rho signaling plays a crucial role in CD44 surface expression. BPs inhibits the mevalonate pathway, which in turn, prevents the prenylation of a number of small GTPases. Attenuation of Rho GTPase activation by BPs may have contributed to the down regulation of cell surface CD44/MMP-9 interaction, MMP-9 activation/secretion, and cell migration. Taken together, these observations suggest that CD44 surface expression is an important event in the activation of MMP-9 and migration of prostate cancer cells. The various steps involved in the above mentioned signaling pathway and/or the molecules regulating the activation of MMP-9 are potential therapeutic target.

• Authors: Bhavik Desai, Michael J Rogers, Meenakshi A Chellaiah
• Journal: Molecular cancer (Mol Cancer) Vol. 6 Pg. 18 (Mar 07 2007) ISSN: 1476-4598 [Electronic] England
• PMID: 17343740 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CD44 protein, human
• Diphosphonates
• Hyaluronan Receptors
• Integrin alphaVbeta3
• Mutant Proteins
• Neoplasm Proteins
• RANK Ligand
• RNA, Small Interfering
• Recombinant Fusion Proteins
• TNFSF11 protein, human
• Osteopontin
• Matrix Metalloproteinase 9
• rho GTP-Binding Proteins
• Mevalonic Acid

Topics

• Adenocarcinoma (genetics, metabolism, pathology, prevention & control, secondary)
• Bone Neoplasms (physiopathology, prevention & control, secondary)
• Cell Adhesion (drug effects, physiology)
• Cell Line, Tumor (metabolism, pathology)
• Cell Movement (drug effects, physiology)
• Diphosphonates (pharmacology, therapeutic use)
• Enzyme Activation (drug effects)
• Giant Cells (metabolism, pathology)
• Humans
• Hyaluronan Receptors (biosynthesis, genetics, physiology)
• Integrin alphaVbeta3 (physiology)
• Male
• Matrix Metalloproteinase 9 (physiology)
• Mevalonic Acid (metabolism)
• Mutant Proteins (physiology)
• Neoplasm Invasiveness
• Neoplasm Metastasis (physiopathology, prevention & control)
• Neoplasm Proteins (biosynthesis, genetics, physiology)
• Osteopontin (biosynthesis, deficiency, genetics, physiology)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Prenylation (drug effects)
• RANK Ligand (biosynthesis, genetics)
• RNA Interference
• RNA, Small Interfering (pharmacology)
• Recombinant Fusion Proteins (physiology)
• Signal Transduction (drug effects, physiology)
• rho GTP-Binding Proteins (physiology)