Ovarian cancer G protein-coupled receptor 1, a new metastasis suppressor gene in prostate cancer

Lisam Shanjukumar Singh, Michael Berk, Rhonda Oates, Zhenwen Zhao, Haiyan Tan, Ying Jiang, Aimin Zhou, Kashif Kirmani, Rosemary Steinmetz, Daniel Lindner, Yan Xu

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Abstract

Background: Metastasis is a process by which tumors spread from primary organs to other sites in the body and is the major cause of death for cancer patients. The ovarian cancer G protein-coupled receptor 1 (OGR1) gene has been shown to be expressed at lower levels in metastatic compared with primary prostate cancer tissues. Methods: We used an orthotopic mouse metastasis model, in which we injected PC3 metastatic human prostate cancer cells stably transfected with empty vector (vector-PC3) or OGR1-expressing vector (OGR1-PC3) into the prostate lobes of athymic or NOD/SCID mice (n = 3-8 mice per group). Migration of PC3 cells transiently transfected with vector control or with OGR1- or GPR4 (a G protein-coupled receptor with the highest homology to OGR1)-expressing vectors was measured in vitro by Boyden chamber assays. G protein alpha-inhibitory subunit 1 (Gαi1) expression after treatment with pertussis toxin (PTX) was measured using immunoblotting analysis. The inhibitory factor present in the conditioned medium was extracted using organic solvents and analyzed by mass spectrometry. Results: In vivo, all 26 mice carrying tumors that were derived from vector-PC3 cells developed prostate cancer metastases (mean = 100%, 95% confidence interval [CI] = 83.97% to 100%) but few (4 of 32) mice carrying tumors derived from OGR1-expressing PC3 cells (mean = 12.50%, 95% CI = 4.08% to 29.93%) developed metastases. However, exogenous OGR1 overexpression had no effect on primary prostate tumor growth in vivo. In vitro, expression of OGR1, but not GPR4, inhibited cell migration (mean percentage of cells migrated, 30.2% versus 100%, difference = 69.8%, 95% CI = 63.0% to 75.9%; P <.001) via increased expression of Gαi1 and the secretion of a chloroform/ methanol-extractable heat-insensitive factor into the conditioned medium through a PTX-sensitive pathway. Conclusion: OGR1 is a novel metastasis suppressor gene for prostate cancer. OGR1's constitutive activity via Gαi contributes to its inhibitory effect on cell migration in vitro.

Original languageEnglish (US)
Pages (from-to)1313-1327
Number of pages15
JournalJournal of the National Cancer Institute
Volume99
Issue number17
DOIs
StatePublished - Sep 5 2007

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G-Protein-Coupled Receptors
Tumor Suppressor Genes
Ovarian Neoplasms
Prostatic Neoplasms
Neoplasm Metastasis
Cell Movement
Pertussis Toxin
Confidence Intervals
Neoplasms
Conditioned Culture Medium
Prostate
GTP-Binding Protein alpha Subunits
Inbred NOD Mouse
SCID Mice
Chloroform
Immunoblotting
Methanol
Cause of Death
Mass Spectrometry
Hot Temperature

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Ovarian cancer G protein-coupled receptor 1, a new metastasis suppressor gene in prostate cancer. / Singh, Lisam Shanjukumar; Berk, Michael; Oates, Rhonda; Zhao, Zhenwen; Tan, Haiyan; Jiang, Ying; Zhou, Aimin; Kirmani, Kashif; Steinmetz, Rosemary; Lindner, Daniel; Xu, Yan.

In: Journal of the National Cancer Institute, Vol. 99, No. 17, 05.09.2007, p. 1313-1327.

Research output: Contribution to journalArticle

Singh, LS, Berk, M, Oates, R, Zhao, Z, Tan, H, Jiang, Y, Zhou, A, Kirmani, K, Steinmetz, R, Lindner, D & Xu, Y 2007, 'Ovarian cancer G protein-coupled receptor 1, a new metastasis suppressor gene in prostate cancer', Journal of the National Cancer Institute, vol. 99, no. 17, pp. 1313-1327. https://doi.org/10.1093/jnci/djm107
Singh, Lisam Shanjukumar ; Berk, Michael ; Oates, Rhonda ; Zhao, Zhenwen ; Tan, Haiyan ; Jiang, Ying ; Zhou, Aimin ; Kirmani, Kashif ; Steinmetz, Rosemary ; Lindner, Daniel ; Xu, Yan. / Ovarian cancer G protein-coupled receptor 1, a new metastasis suppressor gene in prostate cancer. In: Journal of the National Cancer Institute. 2007 ; Vol. 99, No. 17. pp. 1313-1327.
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abstract = "Background: Metastasis is a process by which tumors spread from primary organs to other sites in the body and is the major cause of death for cancer patients. The ovarian cancer G protein-coupled receptor 1 (OGR1) gene has been shown to be expressed at lower levels in metastatic compared with primary prostate cancer tissues. Methods: We used an orthotopic mouse metastasis model, in which we injected PC3 metastatic human prostate cancer cells stably transfected with empty vector (vector-PC3) or OGR1-expressing vector (OGR1-PC3) into the prostate lobes of athymic or NOD/SCID mice (n = 3-8 mice per group). Migration of PC3 cells transiently transfected with vector control or with OGR1- or GPR4 (a G protein-coupled receptor with the highest homology to OGR1)-expressing vectors was measured in vitro by Boyden chamber assays. G protein alpha-inhibitory subunit 1 (Gαi1) expression after treatment with pertussis toxin (PTX) was measured using immunoblotting analysis. The inhibitory factor present in the conditioned medium was extracted using organic solvents and analyzed by mass spectrometry. Results: In vivo, all 26 mice carrying tumors that were derived from vector-PC3 cells developed prostate cancer metastases (mean = 100{\%}, 95{\%} confidence interval [CI] = 83.97{\%} to 100{\%}) but few (4 of 32) mice carrying tumors derived from OGR1-expressing PC3 cells (mean = 12.50{\%}, 95{\%} CI = 4.08{\%} to 29.93{\%}) developed metastases. However, exogenous OGR1 overexpression had no effect on primary prostate tumor growth in vivo. In vitro, expression of OGR1, but not GPR4, inhibited cell migration (mean percentage of cells migrated, 30.2{\%} versus 100{\%}, difference = 69.8{\%}, 95{\%} CI = 63.0{\%} to 75.9{\%}; P <.001) via increased expression of Gαi1 and the secretion of a chloroform/ methanol-extractable heat-insensitive factor into the conditioned medium through a PTX-sensitive pathway. Conclusion: OGR1 is a novel metastasis suppressor gene for prostate cancer. OGR1's constitutive activity via Gαi contributes to its inhibitory effect on cell migration in vitro.",
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AU - Singh, Lisam Shanjukumar

AU - Berk, Michael

AU - Oates, Rhonda

AU - Zhao, Zhenwen

AU - Tan, Haiyan

AU - Jiang, Ying

AU - Zhou, Aimin

AU - Kirmani, Kashif

AU - Steinmetz, Rosemary

AU - Lindner, Daniel

AU - Xu, Yan

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N2 - Background: Metastasis is a process by which tumors spread from primary organs to other sites in the body and is the major cause of death for cancer patients. The ovarian cancer G protein-coupled receptor 1 (OGR1) gene has been shown to be expressed at lower levels in metastatic compared with primary prostate cancer tissues. Methods: We used an orthotopic mouse metastasis model, in which we injected PC3 metastatic human prostate cancer cells stably transfected with empty vector (vector-PC3) or OGR1-expressing vector (OGR1-PC3) into the prostate lobes of athymic or NOD/SCID mice (n = 3-8 mice per group). Migration of PC3 cells transiently transfected with vector control or with OGR1- or GPR4 (a G protein-coupled receptor with the highest homology to OGR1)-expressing vectors was measured in vitro by Boyden chamber assays. G protein alpha-inhibitory subunit 1 (Gαi1) expression after treatment with pertussis toxin (PTX) was measured using immunoblotting analysis. The inhibitory factor present in the conditioned medium was extracted using organic solvents and analyzed by mass spectrometry. Results: In vivo, all 26 mice carrying tumors that were derived from vector-PC3 cells developed prostate cancer metastases (mean = 100%, 95% confidence interval [CI] = 83.97% to 100%) but few (4 of 32) mice carrying tumors derived from OGR1-expressing PC3 cells (mean = 12.50%, 95% CI = 4.08% to 29.93%) developed metastases. However, exogenous OGR1 overexpression had no effect on primary prostate tumor growth in vivo. In vitro, expression of OGR1, but not GPR4, inhibited cell migration (mean percentage of cells migrated, 30.2% versus 100%, difference = 69.8%, 95% CI = 63.0% to 75.9%; P <.001) via increased expression of Gαi1 and the secretion of a chloroform/ methanol-extractable heat-insensitive factor into the conditioned medium through a PTX-sensitive pathway. Conclusion: OGR1 is a novel metastasis suppressor gene for prostate cancer. OGR1's constitutive activity via Gαi contributes to its inhibitory effect on cell migration in vitro.

AB - Background: Metastasis is a process by which tumors spread from primary organs to other sites in the body and is the major cause of death for cancer patients. The ovarian cancer G protein-coupled receptor 1 (OGR1) gene has been shown to be expressed at lower levels in metastatic compared with primary prostate cancer tissues. Methods: We used an orthotopic mouse metastasis model, in which we injected PC3 metastatic human prostate cancer cells stably transfected with empty vector (vector-PC3) or OGR1-expressing vector (OGR1-PC3) into the prostate lobes of athymic or NOD/SCID mice (n = 3-8 mice per group). Migration of PC3 cells transiently transfected with vector control or with OGR1- or GPR4 (a G protein-coupled receptor with the highest homology to OGR1)-expressing vectors was measured in vitro by Boyden chamber assays. G protein alpha-inhibitory subunit 1 (Gαi1) expression after treatment with pertussis toxin (PTX) was measured using immunoblotting analysis. The inhibitory factor present in the conditioned medium was extracted using organic solvents and analyzed by mass spectrometry. Results: In vivo, all 26 mice carrying tumors that were derived from vector-PC3 cells developed prostate cancer metastases (mean = 100%, 95% confidence interval [CI] = 83.97% to 100%) but few (4 of 32) mice carrying tumors derived from OGR1-expressing PC3 cells (mean = 12.50%, 95% CI = 4.08% to 29.93%) developed metastases. However, exogenous OGR1 overexpression had no effect on primary prostate tumor growth in vivo. In vitro, expression of OGR1, but not GPR4, inhibited cell migration (mean percentage of cells migrated, 30.2% versus 100%, difference = 69.8%, 95% CI = 63.0% to 75.9%; P <.001) via increased expression of Gαi1 and the secretion of a chloroform/ methanol-extractable heat-insensitive factor into the conditioned medium through a PTX-sensitive pathway. Conclusion: OGR1 is a novel metastasis suppressor gene for prostate cancer. OGR1's constitutive activity via Gαi contributes to its inhibitory effect on cell migration in vitro.

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