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8-Br-cGMP suppresses tumor progression through EGFR/PLC γ1 pathway in epithelial ovarian cancer
Min Wu1,2, Chunyan Mu2,3, Huiwen Yang2,3
1Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.
Background:
Cyclic guanosine monophosphate (cGMP)-dependent protein kinase I (PKG-I), a serine/threonine kinase, is important in tumor development. The present study determines that the cGMP/PKG I pathway is essential for promoting cell proliferation and survival in human ovarian cancer cells, whereas cGMP analog has been shown to lead to growth inhibition and apoptosis of various cancer cells. The role of cGMP/PKG I pathway in epithelial ovarian cancer (EOC), therefore, remains controversial. We investigated the effect of cGMP/PKG I pathway and the underlying mechanism in EOC.
Methods And Results:
The results showed that exogenous 8-Bromoguanosine-3', 5'-cyclic monophosphate (8-Br-cGMP) (cGMP analog) could antagonize the effects by EGF, including suppressing proliferation, invasion and migration of EOC cells. In vivo, 8-Br-cGMP hampered the growth of the xenograft tumor. Additionally, the expressions of epidermal growth factor receptor (EGFR), matrix metallopeptidase 9 (MMP9), proliferating cell nuclear antigen and Ki67 in xenograft tumor were decreased after 8-Br-cGMP intervention. Further research demonstrated that 8-Br-cGMP decreased the phosphorylation of EGFR (Y992) and downstream proteins phospholipase Cγ1 (PLC γ1) (Y783), calmodulin kinase II (T286) and inhibited cytoplasmic Ca2+ release as well as PKC transferring to cell membrane. It's worth noting that the inhibition was 8-Br-cGMP dose-dependent and 8-Br-cGMP showed similar inhibitory effect on EOC cells compared with U-73122, a specific inhibitor of PLC γ1.
Conclusions:
The activation of endogenous PKG I by addition of exogenous 8-Br-cGMP could inhibit EOC development probably via EGFR/PLCγ1 signaling pathway. 8-Br-cGMP/PKG I provide a new insight and strategy for EOC treatment.
Insights
Cyclic guanosine monophosphate (cGMP)-dependent protein kinase I (PKG-I) activation by 8-Bromoguanosine-3', 5'-cyclic monophosphate (8-Br-cGMP) inhibits ovarian cancer cell growth. This cGMP analog targets the EGFR/PLCγ1 pathway, offering a potential new treatment strategy for epithelial ovarian cancer (EOC).
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cyclic guanosine monophosphate (cGMP)-dependent protein kinase I (PKG-I) plays a role in tumor development.
- The cGMP/PKG I pathway's role in epithelial ovarian cancer (EOC) is controversial, with some studies showing growth promotion and others inhibition.
- This study investigates the specific effects and mechanisms of the cGMP/PKG I pathway in EOC.
Purpose of the Study:
- To investigate the effect of the cGMP/PKG I pathway on human epithelial ovarian cancer (EOC) cells.
- To elucidate the underlying molecular mechanisms by which cGMP analogs impact EOC progression.
- To evaluate the therapeutic potential of targeting the cGMP/PKG I pathway in EOC.
Main Methods:
- Treatment of EOC cells with 8-Bromoguanosine-3", 5"-cyclic monophosphate (8-Br-cGMP), a cGMP analog.
- In vivo studies using xenograft tumor models in mice.
- Analysis of protein expression and phosphorylation, including epidermal growth factor receptor (EGFR) and downstream signaling molecules.
- Assessment of intracellular calcium (Ca2+) levels and protein kinase C (PKC) translocation.
Main Results:
- Exogenous 8-Br-cGMP suppressed EOC cell proliferation, invasion, and migration, antagonizing epidermal growth factor (EGF) effects.
- In vivo, 8-Br-cGMP inhibited xenograft tumor growth and reduced expression of EGFR, matrix metallopeptidase 9 (MMP9), and proliferation markers (Ki67, PCNA).
- 8-Br-cGMP decreased EGFR and phospholipase Cγ1 (PLCγ1) phosphorylation, inhibited Ca2+ release, and reduced PKC translocation, with effects being dose-dependent and comparable to a specific PLCγ1 inhibitor.
Conclusions:
- Activation of endogenous PKG I by 8-Br-cGMP inhibits EOC development, likely through the EGFR/PLCγ1 signaling pathway.
- The findings suggest that the 8-Br-cGMP/PKG I pathway presents a novel therapeutic strategy for epithelial ovarian cancer.
- Targeting the cGMP/PKG I pathway offers a new insight for EOC treatment.
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