Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models

Yingming Li, Robert A. Sikes, Bahaa S. Malaeb, Fan Yeung, Andrew Law, Sarah E. Graham, Min Pei, Chinghai Kao, Joel Nelson, Kenneth S. Koeneman, Leland W K Chung

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Introduction: To investigate the effect of bone environment on cellular proliferation, mature prostate-specific antigen (PSA) production and secretion, and PSA transcriptional regulation of prostate cancer cells. Materials and methods: Androgen-independent C4-2 prostate cancer cells were co-cultured with various osteoblastic cells in a transwell system. Proliferation was measured via cell counting and MTT assay. Lactate and PSA were determined in the conditioned media (CM). Transcriptional activity of the full-length PSA promoter (6.1 kilobases) and of 3 deletion constructs was determined via luciferase reporter assay upon exposure to CM from various osteoblastic cell lines. Results: Osteoblastic bone cells and CM, but not control cells (fibroblast) or CM, reproducibly stimulated the proliferation of C4-2 cells. The co-culture system, PSA production by C4-2 cells transiently decreased when in co-culture with osteoblastic, but not with control cells. After abundant prostate cell proliferation, the secreted PSA levels rose exponentially. Addition of CM from osteoblastic cells, but not control cells, consistently decreased (about 3-fold) the transcriptional activity of the PSA promoter in C4-2 cells. Deletion construct analysis of the PSA promoter revealed that the transcriptional down-regulation is dually controlled by elements close to the TATA and upstream androgen responsive (ARE III) components. Conclusions: The osteoblastic environment stimulates prostate cancer cell proliferation but reduces PSA production initially. The mechanism of PSA down-regulation is transcriptional, most likely in response to soluble factors present in the osteoblastic bone stromal cell CM. Transcriptional down-regulation appears to be mediated by elements near both the TATA box and the ARE III component.

Original languageEnglish
Pages (from-to)802-808
Number of pages7
JournalUrologic Oncology: Seminars and Original Investigations
Volume29
Issue number6
DOIs
StatePublished - Nov 2011

Fingerprint

Prostate-Specific Antigen
Osteoblasts
Prostatic Neoplasms
Down-Regulation
Cell Line
Conditioned Culture Medium
Growth
Cell Proliferation
Coculture Techniques
Bone and Bones
Androgens
TATA Box
Stromal Cells
Luciferases
Prostate
Lactic Acid
Fibroblasts

Keywords

  • Metastasis
  • Osteoblast
  • Prostate neoplasm
  • Prostate-specific antigen
  • Stromal-epithelial interaction

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models. / Li, Yingming; Sikes, Robert A.; Malaeb, Bahaa S.; Yeung, Fan; Law, Andrew; Graham, Sarah E.; Pei, Min; Kao, Chinghai; Nelson, Joel; Koeneman, Kenneth S.; Chung, Leland W K.

In: Urologic Oncology: Seminars and Original Investigations, Vol. 29, No. 6, 11.2011, p. 802-808.

Research output: Contribution to journalArticle

Li, Yingming ; Sikes, Robert A. ; Malaeb, Bahaa S. ; Yeung, Fan ; Law, Andrew ; Graham, Sarah E. ; Pei, Min ; Kao, Chinghai ; Nelson, Joel ; Koeneman, Kenneth S. ; Chung, Leland W K. / Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models. In: Urologic Oncology: Seminars and Original Investigations. 2011 ; Vol. 29, No. 6. pp. 802-808.
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abstract = "Introduction: To investigate the effect of bone environment on cellular proliferation, mature prostate-specific antigen (PSA) production and secretion, and PSA transcriptional regulation of prostate cancer cells. Materials and methods: Androgen-independent C4-2 prostate cancer cells were co-cultured with various osteoblastic cells in a transwell system. Proliferation was measured via cell counting and MTT assay. Lactate and PSA were determined in the conditioned media (CM). Transcriptional activity of the full-length PSA promoter (6.1 kilobases) and of 3 deletion constructs was determined via luciferase reporter assay upon exposure to CM from various osteoblastic cell lines. Results: Osteoblastic bone cells and CM, but not control cells (fibroblast) or CM, reproducibly stimulated the proliferation of C4-2 cells. The co-culture system, PSA production by C4-2 cells transiently decreased when in co-culture with osteoblastic, but not with control cells. After abundant prostate cell proliferation, the secreted PSA levels rose exponentially. Addition of CM from osteoblastic cells, but not control cells, consistently decreased (about 3-fold) the transcriptional activity of the PSA promoter in C4-2 cells. Deletion construct analysis of the PSA promoter revealed that the transcriptional down-regulation is dually controlled by elements close to the TATA and upstream androgen responsive (ARE III) components. Conclusions: The osteoblastic environment stimulates prostate cancer cell proliferation but reduces PSA production initially. The mechanism of PSA down-regulation is transcriptional, most likely in response to soluble factors present in the osteoblastic bone stromal cell CM. Transcriptional down-regulation appears to be mediated by elements near both the TATA box and the ARE III component.",
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T1 - Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models

AU - Li, Yingming

AU - Sikes, Robert A.

AU - Malaeb, Bahaa S.

AU - Yeung, Fan

AU - Law, Andrew

AU - Graham, Sarah E.

AU - Pei, Min

AU - Kao, Chinghai

AU - Nelson, Joel

AU - Koeneman, Kenneth S.

AU - Chung, Leland W K

PY - 2011/11

Y1 - 2011/11

N2 - Introduction: To investigate the effect of bone environment on cellular proliferation, mature prostate-specific antigen (PSA) production and secretion, and PSA transcriptional regulation of prostate cancer cells. Materials and methods: Androgen-independent C4-2 prostate cancer cells were co-cultured with various osteoblastic cells in a transwell system. Proliferation was measured via cell counting and MTT assay. Lactate and PSA were determined in the conditioned media (CM). Transcriptional activity of the full-length PSA promoter (6.1 kilobases) and of 3 deletion constructs was determined via luciferase reporter assay upon exposure to CM from various osteoblastic cell lines. Results: Osteoblastic bone cells and CM, but not control cells (fibroblast) or CM, reproducibly stimulated the proliferation of C4-2 cells. The co-culture system, PSA production by C4-2 cells transiently decreased when in co-culture with osteoblastic, but not with control cells. After abundant prostate cell proliferation, the secreted PSA levels rose exponentially. Addition of CM from osteoblastic cells, but not control cells, consistently decreased (about 3-fold) the transcriptional activity of the PSA promoter in C4-2 cells. Deletion construct analysis of the PSA promoter revealed that the transcriptional down-regulation is dually controlled by elements close to the TATA and upstream androgen responsive (ARE III) components. Conclusions: The osteoblastic environment stimulates prostate cancer cell proliferation but reduces PSA production initially. The mechanism of PSA down-regulation is transcriptional, most likely in response to soluble factors present in the osteoblastic bone stromal cell CM. Transcriptional down-regulation appears to be mediated by elements near both the TATA box and the ARE III component.

AB - Introduction: To investigate the effect of bone environment on cellular proliferation, mature prostate-specific antigen (PSA) production and secretion, and PSA transcriptional regulation of prostate cancer cells. Materials and methods: Androgen-independent C4-2 prostate cancer cells were co-cultured with various osteoblastic cells in a transwell system. Proliferation was measured via cell counting and MTT assay. Lactate and PSA were determined in the conditioned media (CM). Transcriptional activity of the full-length PSA promoter (6.1 kilobases) and of 3 deletion constructs was determined via luciferase reporter assay upon exposure to CM from various osteoblastic cell lines. Results: Osteoblastic bone cells and CM, but not control cells (fibroblast) or CM, reproducibly stimulated the proliferation of C4-2 cells. The co-culture system, PSA production by C4-2 cells transiently decreased when in co-culture with osteoblastic, but not with control cells. After abundant prostate cell proliferation, the secreted PSA levels rose exponentially. Addition of CM from osteoblastic cells, but not control cells, consistently decreased (about 3-fold) the transcriptional activity of the PSA promoter in C4-2 cells. Deletion construct analysis of the PSA promoter revealed that the transcriptional down-regulation is dually controlled by elements close to the TATA and upstream androgen responsive (ARE III) components. Conclusions: The osteoblastic environment stimulates prostate cancer cell proliferation but reduces PSA production initially. The mechanism of PSA down-regulation is transcriptional, most likely in response to soluble factors present in the osteoblastic bone stromal cell CM. Transcriptional down-regulation appears to be mediated by elements near both the TATA box and the ARE III component.

KW - Metastasis

KW - Osteoblast

KW - Prostate neoplasm

KW - Prostate-specific antigen

KW - Stromal-epithelial interaction

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