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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
IGFBP-3 sensitizes prostate cancer cells to interferon-gamma-induced apoptosis
Peng Fang1, Vivian Hwa, Brian M Little
1Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239-3098, USA.
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.
Design:
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.
Insights
Insulin-like growth factor binding protein-3 (IGFBP-3) enhances interferon-gamma (IFN-gamma) effects on prostate cancer cells. This IGFBP-3 action is independent of IGF and involves STAT1 and mTOR signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Insulin-like growth factor binding protein-3 (IGFBP-3) has known IGF-independent roles in cell growth and death.
- Prostate cancer cells exhibit complex responses to growth factors and cytokines.
Purpose of the Study:
- To investigate the role of IGFBP-3 in sensitizing prostate cancer cells to interferon-gamma (IFN-gamma).
- To elucidate the signaling pathways involved in IGFBP-3 and IFN-gamma interactions.
Main Methods:
- Prostate cancer cell lines (M12) were treated with IGFBP-3, IGFBP-1, and/or IFN-gamma.
- Cell proliferation, apoptosis, and signaling pathway activation (STAT1, mTOR) were assessed.
- Mutant IGFBP-3 variants were used to determine the necessity of IGF binding and intracellular localization.
Main Results:
- Co-treatment with IGFBP-3 and IFN-gamma significantly inhibited cell proliferation and induced apoptosis in M12 cells.
- IGFBP-1 did not elicit the same effects when combined with IFN-gamma.
- IGFBP-3 enhanced IFN-gamma-induced STAT1 phosphorylation in an IGF-independent manner.
- Inhibition of the mTOR pathway abrogated IGFBP-3-promoted apoptosis.
Conclusions:
- IGFBP-3 sensitizes prostate cancer cells to the anti-proliferative and proapoptotic effects of IFN-gamma.
- This sensitization occurs via an IGF-independent mechanism involving STAT1 and mTOR signaling.
- IGFBP-3's ability to enhance IFN-gamma's efficacy presents a potential therapeutic avenue in prostate cancer treatment.
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