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Essential role for G proteins in prostate cancer cell growth and signaling
1Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Purpose:
G proteins are involved in the regulation of multiple cellular functions, including metabolism and proliferation. We studied the role of Gi/o protein subunits in the growth and survival of prostate cancer cells.
Materials And Methods:
We investigated the effects of pertussis toxin and the G beta gamma sequestrant peptide G protein coupled receptor kinase 2 carboxy terminus on the growth and mitogenic signaling of prostate cells.
Results:
Pertussis toxin treatment inhibited the lysophosphatidic acid and serum mediated growth of prostate cancer PC-3 cells by 70% to 80% but showed no effect on insulin-like growth factor 1 (IGF-1) or epidermal growth factor (EGF) mediated growth of these cells. Growth and survival of cells are dependent on activation of intracellular signaling cascades, including those of the mitogen activated protein kinase and Akt pathways. Treatment of the PC-3 cells with lysophosphatidic acid, EGF or serum induced an 8-fold increase in the phosphorylation levels of the mitogen activated protein kinases Erk 1 and 2, and a 3-fold increase in the phosphorylation level of Akt. Erk 1/2 and Akt phosphorylation by lysophosphatidic acid and serum was inhibited by pertussis toxin, suggesting a Gi/o subunit dependent mechanism. EGF and IGF-1 mediated increase in phosphorylation of Erk 1/2 and Akt was independent of pertussis toxin action. Expression of the G beta gamma sequestrant peptide G protein coupled receptor kinase 2 carboxy terminus inhibited the lysophosphatidic acid and serum mediated activation of Erk 1/2 and Akt but showed no effect on the IGF-1 or EGF mediated response. Finally, we showed that activation of the Erk 1/2 pathway in the prostate cancer cells by lysophosphatidic acid and serum is dependent on the EGF receptor and c-Src protein tyrosine kinases. Whereas activation of Akt by these stimuli is not dependent on protein tyrosine kinase activation, it is mediated by PI3K.
Conclusions:
These data indicate that lysophosphatidic acid and serum induce proliferation and mitogenic signaling of prostate cancer cells. Importantly, the serum mediated growth of these cells is dependent on Gi beta gamma subunits, suggesting an important regulatory role for G proteins in the growth of prostate cancer cells.
Insights
Gi/o protein subunits regulate prostate cancer cell growth. Pertussis toxin inhibited lysophosphatidic acid and serum-induced growth, highlighting the role of G proteins in prostate cancer proliferation.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Cancer Research
Background:
- G proteins are crucial regulators of cellular functions, including metabolism and proliferation.
- Understanding the role of specific G protein subunits in cancer is essential for targeted therapies.
Purpose of the Study:
- To investigate the role of Gi/o protein subunits in the growth and survival of prostate cancer cells.
- To elucidate the signaling pathways involved in G protein-mediated prostate cancer cell proliferation.
Main Methods:
- Utilized pertussis toxin to inhibit Gi/o protein activity.
- Employed a G beta gamma sequestrant peptide (GRK2ct) to block G beta gamma subunit signaling.
- Assessed prostate cancer cell growth, proliferation, and mitogenic signaling (Erk1/2, Akt phosphorylation) in response to various growth factors and ligands.
Main Results:
- Pertussis toxin significantly inhibited lysophosphatidic acid (LPA) and serum-induced prostate cancer cell growth (70-80%) but not IGF-1 or EGF-mediated growth.
- LPA and serum induced Erk1/2 and Akt phosphorylation, which was blocked by pertussis toxin and GRK2ct, indicating Gi/o and G beta gamma subunit dependence.
- EGF and IGF-1 mediated signaling through Erk1/2 and Akt was independent of pertussis toxin, with EGF signaling involving EGFR and c-Src, and Akt activation by PI3K.
Conclusions:
- LPA and serum stimulate prostate cancer cell proliferation and mitogenic signaling via Gi/o protein-dependent pathways.
- Serum-induced prostate cancer cell growth is critically dependent on Gi beta gamma subunits.
- These findings underscore the significant regulatory role of G proteins in prostate cancer progression and suggest potential therapeutic targets.