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

Bhavik Desai, Michael John Rogers, Meenakshi A Chellaiah

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100 Citations (Scopus)

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.
Original languageEnglish
Article number18
Number of pages16
JournalMolecular Cancer
Volume6
DOIs
Publication statusPublished - 7 Mar 2007

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Keywords

  • adenocarcinoma
  • antigens, CD44
  • bone neoplasms
  • cell adhesion
  • cell line, tumor
  • cell movement
  • diphosphonates
  • enzyme activation
  • giant cells
  • humans
  • integrin alphaVbeta3
  • male
  • matrix metalloproteinase 9
  • mevalonic acid
  • mutant proteins
  • neoplasm invasiveness
  • neoplasm metastasis
  • neoplasm proteins
  • osteopontin
  • prostatic neoplasms
  • protein prenylation
  • RANK ligand
  • RNA interference
  • RNA, small interfering
  • recombinant fusion proteins
  • signal transduction
  • rho GTP-binding proteins

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