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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression
Sun-Hee Kim1, Yuuri Hashimoto1, Sung-Nam Cho2
1Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
COX-2 and its product PGE2 enhance carcinogenesis and tumor progression, which has been previously reported in melanoma. As most COX inhibitors cause much toxicity, the downstream microsomal PGE2 synthase-1 (mPGES1) is a consideration for targeting. Human melanoma TMAs were employed for testing mPGES1 protein staining intensity and percentage levels, and both increased with clinical stage; employing a different Stage III TMA, mPGES1 intensity (not percentage) associated with reduced patient survival. Our results further show that iNOS was also highly expressed in melanoma tissues with high mPGES1 levels, and iNOS-mediated NO promoted mPGES1 expression and PGE2 production. An mPGES1-specific inhibitor (CAY10526) as well as siRNA attenuated cell survival and increased apoptosis. CAY10526 significantly suppressed tumor growth and increased apoptosis in melanoma xenografts. Our findings support the value of a prognostic and predictive role for mPGES1, and suggest targeting this molecule in the PGE2 pathway as another avenue toward improving melanoma therapy.
Insights
Targeting microsomal prostaglandin E2 synthase-1 (mPGES1) shows promise for melanoma treatment. Inhibiting mPGES1 reduces tumor growth and increases apoptosis, suggesting its potential as a prognostic and therapeutic target.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) are implicated in melanoma progression.
- Microsomal prostaglandin E2 synthase-1 (mPGES1) is a key enzyme in PGE2 synthesis and a potential therapeutic target due to toxicity of COX inhibitors.
Purpose of the Study:
- To investigate the role of mPGES1 in melanoma progression and its potential as a therapeutic target.
- To explore the relationship between mPGES1, inducible nitric oxide synthase (iNOS), and patient survival.
Main Methods:
- Analysis of mPGES1 protein expression in human melanoma tissue microarrays (TMAs) correlated with clinical stage and patient survival.
- Investigation of the interplay between iNOS and mPGES1 in melanoma cells.
- Evaluation of an mPGES1 inhibitor (CAY10526) and siRNA in vitro and in melanoma xenograft models.
Main Results:
- mPGES1 expression increased with melanoma clinical stage and was associated with reduced survival in Stage III melanoma.
- iNOS was highly expressed in melanoma with high mPGES1 levels, and iNOS-mediated nitric oxide (NO) enhanced mPGES1 expression and PGE2 production.
- Inhibition of mPGES1 using CAY10526 or siRNA reduced melanoma cell survival and increased apoptosis; CAY10526 suppressed tumor growth in vivo.
Conclusions:
- mPGES1 has significant prognostic and predictive value in melanoma.
- Targeting mPGES1 represents a promising therapeutic strategy for improving melanoma treatment outcomes.
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