title: Activation of the MEK-S6 pathway in high-grade ovarian cancers.
abstract: The primary objective of this study is to show the activation and analyze the regulation of the MEK- S6 kinase pathway in high-grade ovarian cancer. Phospho-ERK (pERK), a direct substrate of MEK and 2 phosphorylation sites on the ribosomal protein, S6, Ser235/236, and Ser240/244, which are both targeted by the MEK and PI3-kinase/AKT pathways, were analyzed in 13 cell lines, 28 primary cancers and 8 cases of cancer cells from ascites. In primary cancers, ERK and S6 phosphorylation was measured by immunohistochemistry (IHC). pERK, pS6, pAKT, and p4EBP1 were also measured by Western blotting (WB). The regulation of S6 phosphorylation by the MEK and PI3-kinase pathways was determined in ovarian cancer cell lines. We observed frequent pERK expression in primary ovarian cancers (100% by WB, 75% by IHC) but not in ovarian cancer cells from ascites (25% of cases by WB). The activation of the AKT pathway, measured by pAKT expression occurred in 7 cases of primary ovarian cancer by WB, but in none of the ascites samples. In ovarian cancer cell lines, the MEK pathway had a greater effect on S6 phosphorylation in cells without hyperactive AKT signaling. Our data suggest that MEK is a potential drug target in high-grade ovarian cancer, however, cancer cells with hyperactive AKT and cancer cells in ascites may be less responsive to MEK inhibition. The phosphorylation of S6 as a specific biomarker for either MEK or PI3-kinase pathway activation should be used with caution.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
authors.forename: Aviva P
authors.initials: AP
authors.lastname: Ventura
authors.forename: Sabarinath
authors.initials: S
authors.lastname: Radhakrishnan
authors.forename: Ann
authors.initials: A
authors.lastname: Green
authors.forename: Sunitha K
authors.initials: SK
authors.lastname: Rajaram
authors.forename: April N
authors.initials: AN
authors.lastname: Allen
authors.forename: Kathy
authors.initials: K
authors.lastname: O'Briant
authors.forename: Michèl
authors.initials: M
authors.lastname: Schummer
authors.forename: Beth
authors.initials: B
authors.lastname: Karlan
authors.forename: Nicole
authors.initials: N
authors.lastname: Urban
authors.forename: Muneesh
authors.initials: M
authors.lastname: Tewari
authors.forename: Charles
authors.initials: C
authors.lastname: Drescher
authors.forename: Beatrice S
authors.initials: BS
authors.lastname: Knudsen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001201:Ascites; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D010053:Ovary / Q000378:metabolism* / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases