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


CONCLUSIONS
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.
Desai
Bhavik
B
Department of Biomedical Sciences, Dental School, University of Maryland, Baltimore, MD 21201, USA. bdesa002@umaryland.edu
Rogers
Michael J
MJ
Chellaiah
Meenakshi A
MA
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D001859:Bone Neoplasms / Q000503:physiopathology / Q000517:prevention & control / Q000556:secondary; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects; D015726:Giant Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D039302:Integrin alphaVbeta3 / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D008798:Mevalonic Acid / Q000378:metabolism; D050505:Mutant Proteins / Q000502:physiology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000503:physiopathology* / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053495:Osteopontin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017368:Protein Prenylation / Q000187:drug effects; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000502:physiology
C497483:CD44 protein, human; D004164:Diphosphonates; D018960:Hyaluronan Receptors; D039302:Integrin alphaVbeta3; D050505:Mutant Proteins; D009363:Neoplasm Proteins; D053245:RANK Ligand; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C505688:TNFSF11 protein, human; D053495:Osteopontin; D020780:Matrix Metalloproteinase 9; D020741:rho GTP-Binding Proteins; D008798:Mevalonic Acid