IGFBP-3 sensitizes prostate cancer cells to interferon-gamma-induced apoptosis.
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-gamma)-induced apoptosis and inhibition of cell proliferation.


METHODS
The cell growth or cell death of prostate cells in response to the treatments of IGFBPs and/or IFN-gamma 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 microg/ml), IGFBP-1 (1-5 microg/ml) or IFN-gamma (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-gamma, but not with IGFBP-1 and IFN-gamma. 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-gamma (20 U/ml) alone. The IGFBP-3-promoted apoptosis in the presence of IFN-gamma 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-gamma through an IGF-independent, STAT1- and mTOR-dependent mechanism.
Fang
Peng
P
Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239-3098, USA.
Hwa
Vivian
V
Little
Brian M
BM
Rosenfeld
Ron G
RG
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014443:Tyrosine; D007371:Interferon-gamma; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases