title: pERK 1/2 inhibit Caspase-8 induced apoptosis in cancer cells by phosphorylating it in a cell cycle specific manner.
abstract: ERK 1/2 are found to be hyperactive in many cancers. Active ERK 1/2 (pERK 1/2) are known to protect cancer cells from undergoing death receptor-mediated apoptosis, although the mechanism(s) behind this is poorly understood. Through in vitro kinase assays and mass-spectrometry we demonstrate that pERK 1/2 can phosphorylate pro-Caspase-8 at S387. Also, in EGFR-overexpressing Type I and II ovarian and breast cancer cell lines respectively, ERK 1/2 remain active only during the interphase. During this period, pERK 1/2 could inhibit Trail-induced apoptosis, most effectively during the G1/S phase. By knocking-down the endogenous pro-Caspase-8 using RNAi and replacing it with its non-phosphorylatable counterpart (S387A), a significant increase in Caspase-8 activity upon Trail stimulation was observed, even in the presence of pERK 1/2. Taken together, we propose that a combination of Trail and an inhibitor of ERK 1/2 activities could potentially enhance of Trail's effectiveness as an anti-cancer agent in ERK 1/2 hyperactive cancer cells.
authors.affiliation: Department of Gynaecology and Obstetrics, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Ranadip
authors.initials: R
authors.lastname: Mandal
authors.affiliation: Department of Gynaecology and Obstetrics, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; Clinic and Polyclinic for Ear, Nose and Throat, UKE Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Raab
authors.affiliation: Department of Gynaecology and Obstetrics, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Yves
authors.initials: Y
authors.lastname: Matthess
authors.affiliation: Department of Gynaecology and Obstetrics, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Becker
authors.affiliation: Clinic and Polyclinic for Ear, Nose and Throat, UKE Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Rainald
authors.initials: R
authors.lastname: Knecht
authors.affiliation: Department of Gynaecology and Obstetrics, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: strebhardt@em.uni-frankfurt.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebhardt
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D053181:Caspase 8; D002453:Cell Cycle; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: Apoptosis; Caspase-8; Cell-cycle; pERK 1/2