Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases

F. Margheri, S. D'Alessio, S. Serratí, M. Pucci, F. Annunziato, L. Cosmi, F. Liotta, R. Angeli, A. Angelucci, G. L. Gravina, N. Rucci, M. Bologna, A. Teti, B. Monia, G. Fibbi, M. Del Rosso

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

An important factor implicated in tumor cell predisposition for invasion and metastasis is the malignancy-related upregulation of urokinase plasminogen activator receptor (uPAR). uPAR signals by activating different tyrosine kinases in different cells. We examined the effects of inhibiting uPAR signaling by inhibition of uPAR expression with antisense oligonucleotides (aODNs) in PC3 human prostate cancer cells and evaluated aODN effect in a mouse model of prostate cancer bone metastasis. Following uPAR aODN treatment, PC3 cells exhibited a strong decrease in uPAR expression, evaluated by flow cytometry and by polymerase chain reaction, and of FAK/JNK/Jun phosphorylation. The synthesis of cyclins A, B, D1 and D3 was inhibited, as shown by Western blotting, flow cytometry and polymerase chain reaction, and PC3 cells accumulated in the G2 phase of the cell cycle. PC3 cells' adhesion was unaffected, while proliferation and invasion of Matrigel were impaired. A total of 60 mice were subjected to intracardiac injection of PC3 cells and were randomly assigned to three groups: aODN (treated with 0.5mg intraperitoneum/mouse/day), dODN (treated with the same amounts of a degenerated ODN) and control (injected with a saline solution). At 28 days after heart injection, mice were subjected to a digital scan of total body radiography, which revealed 80% reduction in mice affected by bone metastasis. The use of uPAR aODNs produced a substantial prophylactic effect against prostate cancer bone metastasis, which has to be ascribed to downregulation of uPAR expression.

Original languageEnglish
Pages (from-to)702-714
Number of pages13
JournalGene Therapy
Volume12
Issue number8
DOIs
Publication statusPublished - Apr 2005

Fingerprint

Urokinase Plasminogen Activator Receptors
Bone Neoplasms
Antisense Oligonucleotides
Urokinase-Type Plasminogen Activator
Prostatic Neoplasms
Theoretical Models
Neoplasm Metastasis
Flow Cytometry
Cyclin D3
Cyclin B
Cyclin A
Polymerase Chain Reaction
Injections
G2 Phase
Cell Adhesion
Sodium Chloride
Radiography
Protein-Tyrosine Kinases
Neoplasms
Cell Cycle

Keywords

  • Antisense oligonucleotides
  • Bone metastasis
  • CD87
  • Prostate cancer
  • uPAR

ASJC Scopus subject areas

  • Genetics

Cite this

Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases. / Margheri, F.; D'Alessio, S.; Serratí, S.; Pucci, M.; Annunziato, F.; Cosmi, L.; Liotta, F.; Angeli, R.; Angelucci, A.; Gravina, G. L.; Rucci, N.; Bologna, M.; Teti, A.; Monia, B.; Fibbi, G.; Del Rosso, M.

In: Gene Therapy, Vol. 12, No. 8, 04.2005, p. 702-714.

Research output: Contribution to journalArticle

Margheri, F, D'Alessio, S, Serratí, S, Pucci, M, Annunziato, F, Cosmi, L, Liotta, F, Angeli, R, Angelucci, A, Gravina, GL, Rucci, N, Bologna, M, Teti, A, Monia, B, Fibbi, G & Del Rosso, M 2005, 'Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases', Gene Therapy, vol. 12, no. 8, pp. 702-714. https://doi.org/10.1038/sj.gt.3302456
Margheri, F. ; D'Alessio, S. ; Serratí, S. ; Pucci, M. ; Annunziato, F. ; Cosmi, L. ; Liotta, F. ; Angeli, R. ; Angelucci, A. ; Gravina, G. L. ; Rucci, N. ; Bologna, M. ; Teti, A. ; Monia, B. ; Fibbi, G. ; Del Rosso, M. / Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases. In: Gene Therapy. 2005 ; Vol. 12, No. 8. pp. 702-714.
@article{35efb55635cc4ec6bc0de30709448bae,
title = "Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases",
abstract = "An important factor implicated in tumor cell predisposition for invasion and metastasis is the malignancy-related upregulation of urokinase plasminogen activator receptor (uPAR). uPAR signals by activating different tyrosine kinases in different cells. We examined the effects of inhibiting uPAR signaling by inhibition of uPAR expression with antisense oligonucleotides (aODNs) in PC3 human prostate cancer cells and evaluated aODN effect in a mouse model of prostate cancer bone metastasis. Following uPAR aODN treatment, PC3 cells exhibited a strong decrease in uPAR expression, evaluated by flow cytometry and by polymerase chain reaction, and of FAK/JNK/Jun phosphorylation. The synthesis of cyclins A, B, D1 and D3 was inhibited, as shown by Western blotting, flow cytometry and polymerase chain reaction, and PC3 cells accumulated in the G2 phase of the cell cycle. PC3 cells' adhesion was unaffected, while proliferation and invasion of Matrigel were impaired. A total of 60 mice were subjected to intracardiac injection of PC3 cells and were randomly assigned to three groups: aODN (treated with 0.5mg intraperitoneum/mouse/day), dODN (treated with the same amounts of a degenerated ODN) and control (injected with a saline solution). At 28 days after heart injection, mice were subjected to a digital scan of total body radiography, which revealed 80{\%} reduction in mice affected by bone metastasis. The use of uPAR aODNs produced a substantial prophylactic effect against prostate cancer bone metastasis, which has to be ascribed to downregulation of uPAR expression.",
keywords = "Antisense oligonucleotides, Bone metastasis, CD87, Prostate cancer, uPAR",
author = "F. Margheri and S. D'Alessio and S. Serrat{\'i} and M. Pucci and F. Annunziato and L. Cosmi and F. Liotta and R. Angeli and A. Angelucci and Gravina, {G. L.} and N. Rucci and M. Bologna and A. Teti and B. Monia and G. Fibbi and {Del Rosso}, M.",
year = "2005",
month = "4",
doi = "10.1038/sj.gt.3302456",
language = "English",
volume = "12",
pages = "702--714",
journal = "Gene Therapy",
issn = "0969-7128",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases

AU - Margheri, F.

AU - D'Alessio, S.

AU - Serratí, S.

AU - Pucci, M.

AU - Annunziato, F.

AU - Cosmi, L.

AU - Liotta, F.

AU - Angeli, R.

AU - Angelucci, A.

AU - Gravina, G. L.

AU - Rucci, N.

AU - Bologna, M.

AU - Teti, A.

AU - Monia, B.

AU - Fibbi, G.

AU - Del Rosso, M.

PY - 2005/4

Y1 - 2005/4

N2 - An important factor implicated in tumor cell predisposition for invasion and metastasis is the malignancy-related upregulation of urokinase plasminogen activator receptor (uPAR). uPAR signals by activating different tyrosine kinases in different cells. We examined the effects of inhibiting uPAR signaling by inhibition of uPAR expression with antisense oligonucleotides (aODNs) in PC3 human prostate cancer cells and evaluated aODN effect in a mouse model of prostate cancer bone metastasis. Following uPAR aODN treatment, PC3 cells exhibited a strong decrease in uPAR expression, evaluated by flow cytometry and by polymerase chain reaction, and of FAK/JNK/Jun phosphorylation. The synthesis of cyclins A, B, D1 and D3 was inhibited, as shown by Western blotting, flow cytometry and polymerase chain reaction, and PC3 cells accumulated in the G2 phase of the cell cycle. PC3 cells' adhesion was unaffected, while proliferation and invasion of Matrigel were impaired. A total of 60 mice were subjected to intracardiac injection of PC3 cells and were randomly assigned to three groups: aODN (treated with 0.5mg intraperitoneum/mouse/day), dODN (treated with the same amounts of a degenerated ODN) and control (injected with a saline solution). At 28 days after heart injection, mice were subjected to a digital scan of total body radiography, which revealed 80% reduction in mice affected by bone metastasis. The use of uPAR aODNs produced a substantial prophylactic effect against prostate cancer bone metastasis, which has to be ascribed to downregulation of uPAR expression.

AB - An important factor implicated in tumor cell predisposition for invasion and metastasis is the malignancy-related upregulation of urokinase plasminogen activator receptor (uPAR). uPAR signals by activating different tyrosine kinases in different cells. We examined the effects of inhibiting uPAR signaling by inhibition of uPAR expression with antisense oligonucleotides (aODNs) in PC3 human prostate cancer cells and evaluated aODN effect in a mouse model of prostate cancer bone metastasis. Following uPAR aODN treatment, PC3 cells exhibited a strong decrease in uPAR expression, evaluated by flow cytometry and by polymerase chain reaction, and of FAK/JNK/Jun phosphorylation. The synthesis of cyclins A, B, D1 and D3 was inhibited, as shown by Western blotting, flow cytometry and polymerase chain reaction, and PC3 cells accumulated in the G2 phase of the cell cycle. PC3 cells' adhesion was unaffected, while proliferation and invasion of Matrigel were impaired. A total of 60 mice were subjected to intracardiac injection of PC3 cells and were randomly assigned to three groups: aODN (treated with 0.5mg intraperitoneum/mouse/day), dODN (treated with the same amounts of a degenerated ODN) and control (injected with a saline solution). At 28 days after heart injection, mice were subjected to a digital scan of total body radiography, which revealed 80% reduction in mice affected by bone metastasis. The use of uPAR aODNs produced a substantial prophylactic effect against prostate cancer bone metastasis, which has to be ascribed to downregulation of uPAR expression.

KW - Antisense oligonucleotides

KW - Bone metastasis

KW - CD87

KW - Prostate cancer

KW - uPAR

UR - http://www.scopus.com/inward/record.url?scp=20244381689&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20244381689&partnerID=8YFLogxK

U2 - 10.1038/sj.gt.3302456

DO - 10.1038/sj.gt.3302456

M3 - Article

VL - 12

SP - 702

EP - 714

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 8

ER -