IGFBP-3 sensitizes prostate cancer cells to interferon-gamma-induced apoptosis

Peng Fang, Vivian Hwa, Brian M. Little, Ronald (Ron) Rosenfeld

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Objective: Insulin-like growth factor binding protein-3 (IGFBP-3) has been shown to exhibit diverse biological actions, including IGF-independent effects on cell growth and cell death. Here we report that IGFBP-3 sensitizes prostate cancer cells to interferon-gamma (IFN-γ)-induced apoptosis and inhibition of cell proliferation. Design: The cell growth or cell death of prostate cells in response to the treatments of IGFBPs and/or IFN-γ was measured, and the signaling pathways mediating these actions assessed. Results: Cell proliferation was minimally affected when M12 prostate cancer cells were treated with exogenous IGFBP-3 (1-5 μg/ml), IGFBP-1 (1-5 μg/ml) or IFN-γ (20 U/ml). However, strong inhibition of cell growth and significant apoptosis were observed when M12 cells were co-treated with IGFBP-3 and IFN-γ, but not with IGFBP-1 and IFN-γ. These effects were IGF-independent and appear not to require intracellular localization of IGFBP-3, as similar results were obtained with mutants of IGFBP-3 that either could not bind IGF or has impaired ability to be internalized. Further analyses revealed that IGFBP-3, but not IGFBP-1, could significantly enhance the weak tyrosine phosphorylation of STAT1 induced by IFN-γ (20 U/ml) alone. The IGFBP-3-promoted apoptosis in the presence of IFN-γ could also be abrogated by blockade of the mTOR pathway with its pharmacological inhibitors, LY294002 or rapamycin. Conclusions: These results demonstrated that in a cancer cell line not responsive to exogenous IGFBP-3 alone, IGFBP-3 sensitized the cells to the anti-proliferative, proapoptotic actions of IFN-γ through an IGF-independent, STAT1- and mTOR-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)38-46
Number of pages9
JournalGrowth Hormone and IGF Research
Volume18
Issue number1
DOIs
StatePublished - Feb 2008

Fingerprint

Insulin-Like Growth Factor Binding Protein 3
Interferon-gamma
Prostatic Neoplasms
Apoptosis
Insulin-Like Growth Factor Binding Protein 1
Cell Death
Growth
Cell Proliferation
Insulin-Like Growth Factor Binding Proteins
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Sirolimus
Tyrosine
Prostate
Phosphorylation
Pharmacology
Cell Line

Keywords

  • Apoptosis
  • IGFBP-3
  • Interferon-gamma
  • mTOR
  • Prostate cancer
  • STAT1

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

IGFBP-3 sensitizes prostate cancer cells to interferon-gamma-induced apoptosis. / Fang, Peng; Hwa, Vivian; Little, Brian M.; Rosenfeld, Ronald (Ron).

In: Growth Hormone and IGF Research, Vol. 18, No. 1, 02.2008, p. 38-46.

Research output: Contribution to journalArticle

Fang, Peng ; Hwa, Vivian ; Little, Brian M. ; Rosenfeld, Ronald (Ron). / IGFBP-3 sensitizes prostate cancer cells to interferon-gamma-induced apoptosis. In: Growth Hormone and IGF Research. 2008 ; Vol. 18, No. 1. pp. 38-46.
@article{0a174b0ad6224519add26d98a1df5835,
title = "IGFBP-3 sensitizes prostate cancer cells to interferon-gamma-induced apoptosis",
abstract = "Objective: Insulin-like growth factor binding protein-3 (IGFBP-3) has been shown to exhibit diverse biological actions, including IGF-independent effects on cell growth and cell death. Here we report that IGFBP-3 sensitizes prostate cancer cells to interferon-gamma (IFN-γ)-induced apoptosis and inhibition of cell proliferation. Design: The cell growth or cell death of prostate cells in response to the treatments of IGFBPs and/or IFN-γ was measured, and the signaling pathways mediating these actions assessed. Results: Cell proliferation was minimally affected when M12 prostate cancer cells were treated with exogenous IGFBP-3 (1-5 μg/ml), IGFBP-1 (1-5 μg/ml) or IFN-γ (20 U/ml). However, strong inhibition of cell growth and significant apoptosis were observed when M12 cells were co-treated with IGFBP-3 and IFN-γ, but not with IGFBP-1 and IFN-γ. These effects were IGF-independent and appear not to require intracellular localization of IGFBP-3, as similar results were obtained with mutants of IGFBP-3 that either could not bind IGF or has impaired ability to be internalized. Further analyses revealed that IGFBP-3, but not IGFBP-1, could significantly enhance the weak tyrosine phosphorylation of STAT1 induced by IFN-γ (20 U/ml) alone. The IGFBP-3-promoted apoptosis in the presence of IFN-γ could also be abrogated by blockade of the mTOR pathway with its pharmacological inhibitors, LY294002 or rapamycin. Conclusions: These results demonstrated that in a cancer cell line not responsive to exogenous IGFBP-3 alone, IGFBP-3 sensitized the cells to the anti-proliferative, proapoptotic actions of IFN-γ through an IGF-independent, STAT1- and mTOR-dependent mechanism.",
keywords = "Apoptosis, IGFBP-3, Interferon-gamma, mTOR, Prostate cancer, STAT1",
author = "Peng Fang and Vivian Hwa and Little, {Brian M.} and Rosenfeld, {Ronald (Ron)}",
year = "2008",
month = "2",
doi = "10.1016/j.ghir.2007.07.002",
language = "English (US)",
volume = "18",
pages = "38--46",
journal = "Endocrinology and Metabolism, Supplement",
issn = "1096-6374",
publisher = "Churchill Livingstone",
number = "1",

}

TY - JOUR

T1 - IGFBP-3 sensitizes prostate cancer cells to interferon-gamma-induced apoptosis

AU - Fang, Peng

AU - Hwa, Vivian

AU - Little, Brian M.

AU - Rosenfeld, Ronald (Ron)

PY - 2008/2

Y1 - 2008/2

N2 - Objective: Insulin-like growth factor binding protein-3 (IGFBP-3) has been shown to exhibit diverse biological actions, including IGF-independent effects on cell growth and cell death. Here we report that IGFBP-3 sensitizes prostate cancer cells to interferon-gamma (IFN-γ)-induced apoptosis and inhibition of cell proliferation. Design: The cell growth or cell death of prostate cells in response to the treatments of IGFBPs and/or IFN-γ was measured, and the signaling pathways mediating these actions assessed. Results: Cell proliferation was minimally affected when M12 prostate cancer cells were treated with exogenous IGFBP-3 (1-5 μg/ml), IGFBP-1 (1-5 μg/ml) or IFN-γ (20 U/ml). However, strong inhibition of cell growth and significant apoptosis were observed when M12 cells were co-treated with IGFBP-3 and IFN-γ, but not with IGFBP-1 and IFN-γ. These effects were IGF-independent and appear not to require intracellular localization of IGFBP-3, as similar results were obtained with mutants of IGFBP-3 that either could not bind IGF or has impaired ability to be internalized. Further analyses revealed that IGFBP-3, but not IGFBP-1, could significantly enhance the weak tyrosine phosphorylation of STAT1 induced by IFN-γ (20 U/ml) alone. The IGFBP-3-promoted apoptosis in the presence of IFN-γ could also be abrogated by blockade of the mTOR pathway with its pharmacological inhibitors, LY294002 or rapamycin. Conclusions: These results demonstrated that in a cancer cell line not responsive to exogenous IGFBP-3 alone, IGFBP-3 sensitized the cells to the anti-proliferative, proapoptotic actions of IFN-γ through an IGF-independent, STAT1- and mTOR-dependent mechanism.

AB - Objective: Insulin-like growth factor binding protein-3 (IGFBP-3) has been shown to exhibit diverse biological actions, including IGF-independent effects on cell growth and cell death. Here we report that IGFBP-3 sensitizes prostate cancer cells to interferon-gamma (IFN-γ)-induced apoptosis and inhibition of cell proliferation. Design: The cell growth or cell death of prostate cells in response to the treatments of IGFBPs and/or IFN-γ was measured, and the signaling pathways mediating these actions assessed. Results: Cell proliferation was minimally affected when M12 prostate cancer cells were treated with exogenous IGFBP-3 (1-5 μg/ml), IGFBP-1 (1-5 μg/ml) or IFN-γ (20 U/ml). However, strong inhibition of cell growth and significant apoptosis were observed when M12 cells were co-treated with IGFBP-3 and IFN-γ, but not with IGFBP-1 and IFN-γ. These effects were IGF-independent and appear not to require intracellular localization of IGFBP-3, as similar results were obtained with mutants of IGFBP-3 that either could not bind IGF or has impaired ability to be internalized. Further analyses revealed that IGFBP-3, but not IGFBP-1, could significantly enhance the weak tyrosine phosphorylation of STAT1 induced by IFN-γ (20 U/ml) alone. The IGFBP-3-promoted apoptosis in the presence of IFN-γ could also be abrogated by blockade of the mTOR pathway with its pharmacological inhibitors, LY294002 or rapamycin. Conclusions: These results demonstrated that in a cancer cell line not responsive to exogenous IGFBP-3 alone, IGFBP-3 sensitized the cells to the anti-proliferative, proapoptotic actions of IFN-γ through an IGF-independent, STAT1- and mTOR-dependent mechanism.

KW - Apoptosis

KW - IGFBP-3

KW - Interferon-gamma

KW - mTOR

KW - Prostate cancer

KW - STAT1

UR - http://www.scopus.com/inward/record.url?scp=39049111545&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39049111545&partnerID=8YFLogxK

U2 - 10.1016/j.ghir.2007.07.002

DO - 10.1016/j.ghir.2007.07.002

M3 - Article

C2 - 17719815

AN - SCOPUS:39049111545

VL - 18

SP - 38

EP - 46

JO - Endocrinology and Metabolism, Supplement

JF - Endocrinology and Metabolism, Supplement

SN - 1096-6374

IS - 1

ER -