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

Bhavik Desai, Michael John Rogers, Meenakshi A Chellaiah

Research output: Contribution to journalArticle

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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Osteopontin
Matrix Metalloproteinases
Prostatic Neoplasms
Conditioned Culture Medium
Cell Movement
Down-Regulation
Integrin alphaVbeta3
Prenylation
Cell Line
Mevalonic Acid
rho GTP-Binding Proteins
Monomeric GTP-Binding Proteins
Diphosphonates
Giant Cells
Integrins
Western Blotting
Binding Sites
Ligands

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

Cite this

Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells. / Desai, Bhavik; Rogers, Michael John; Chellaiah, Meenakshi A.

In: Molecular Cancer, Vol. 6, 18, 07.03.2007.

Research output: Contribution to journalArticle

Desai, Bhavik ; Rogers, Michael John ; Chellaiah, Meenakshi A. / Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells. In: Molecular Cancer. 2007 ; Vol. 6.
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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.",
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",
author = "Bhavik Desai and Rogers, {Michael John} and Chellaiah, {Meenakshi A}",
year = "2007",
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language = "English",
volume = "6",
journal = "Molecular Cancer",
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T1 - Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells

AU - Desai, Bhavik

AU - Rogers, Michael John

AU - Chellaiah, Meenakshi A

PY - 2007/3/7

Y1 - 2007/3/7

N2 - 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.

AB - 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.

KW - adenocarcinoma

KW - antigens, CD44

KW - bone neoplasms

KW - cell adhesion

KW - cell line, tumor

KW - cell movement

KW - diphosphonates

KW - enzyme activation

KW - giant cells

KW - humans

KW - integrin alphaVbeta3

KW - male

KW - matrix metalloproteinase 9

KW - mevalonic acid

KW - mutant proteins

KW - neoplasm invasiveness

KW - neoplasm metastasis

KW - neoplasm proteins

KW - osteopontin

KW - prostatic neoplasms

KW - protein prenylation

KW - RANK ligand

KW - RNA interference

KW - RNA, small interfering

KW - recombinant fusion proteins

KW - signal transduction

KW - rho GTP-binding proteins

U2 - 10.1186/1476-4598-6-18

DO - 10.1186/1476-4598-6-18

M3 - Article

C2 - 17343740

VL - 6

JO - Molecular Cancer

JF - Molecular Cancer

SN - 1476-4598

M1 - 18

ER -