title: Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression.
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.
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yuuri
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sung-Nam
authors.initials: SN
authors.lastname: Cho
authors.affiliation: Department of Melanoma Medical Oncology and Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Denái R
authors.initials: DR
authors.lastname: Milton
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Fulya
authors.initials: F
authors.lastname: Dal
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perlman School of Medicine at University of Pennsylvania at University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sangwon F
authors.initials: SF
authors.lastname: Kim
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Menter
authors.affiliation: Department of General Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Suhendan
authors.initials: S
authors.lastname: Ekmekcioglu
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grimm
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology*; D008819:Mice, Nude; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000071876:Prostaglandin-E Synthases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020030:Nitric Oxide Donors; D052247:Nitric Oxide Synthase Type II; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone
keywords: cell survival; inducible nitric oxide synthase; inflammation; melanoma; microsomal PGE2 synthase-1; prostaglandin E2