title: MAPK15 upregulation promotes cell proliferation and prevents DNA damage in male germ cell tumors.
abstract: Germ cell tumors (GCT) are the most common malignancies in males between 15 and 35 years of age. Despite the high cure rate, achieved through chemotherapy and/or surgery, the molecular basis of GCT etiology is still largely obscure. Here, we show a positive correlation between MAPK15 (ERK8; ERK7) expression and specific GCT subtypes, with the highest levels found in the aggressive embryonal carcinomas (EC). Indeed, in corresponding cellular models for EC, MAPK15 enhanced tumorigenicity in vivo and promoted cell proliferation in vitro, supporting a role for this kinase in human GCT. At molecular level, we demonstrated that endogenous MAPK15 is necessary to sustain cell cycle progression of EC cells, by limiting p53 activation and preventing the triggering of p53-dependent mechanisms resulting in cell cycle arrest.To understand MAPK15-dependent mechanisms impinging on p53 activation, we demonstrate that this kinase efficiently protects cells from DNA damage. Moreover, we show that the ability of MAPK15 to control the autophagic process is necessary for basal management of DNA damage and for tumor formation controlled by the kinase.In conclusion, our findings suggest that MAPK15 overexpression may contribute to the malignant transformation of germ cells by controlling a "stress support" autophagic pathway, able to prevent DNA damage and the consequent activation of the p53 tumor suppressor. Moreover, in light of these results, MAPK15-specific inhibitors might represent new tools to enhance the therapeutic index of cytotoxic therapy in GCT treatment, and to increase the sensitivity to DNA-damaging drugs in other chemotherapy-resistant human tumors.
authors.affiliation: Istituto Toscano Tumori (ITT), Core Research Laboratory (CRL), AOU Senese, Siena, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Istituto Toscano Tumori (ITT), Core Research Laboratory (CRL), AOU Senese, Siena, Italy.|Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), Siena, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Colecchia
authors.affiliation: Dipartimento di Scienze Biomediche Avanzate, Università di Napoli "Federico II", Napoli, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ilardi
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Acunzo
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Nigita
authors.affiliation: Istituto Toscano Tumori (ITT), Core Research Laboratory (CRL), AOU Senese, Siena, Italy.|Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), Siena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Sasdelli
authors.affiliation: Istituto di Endocrinologia e Oncologia Sperimentale "G. Salvatore", CNR, Napoli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Celetti
authors.affiliation: Istituto Toscano Tumori (ITT), Core Research Laboratory (CRL), AOU Senese, Siena, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Strambi
authors.affiliation: Dipartimento di Scienze Biomediche Avanzate, Università di Napoli "Federico II", Napoli, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Staibano
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Carlo Maria
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Istituto Toscano Tumori (ITT), Core Research Laboratory (CRL), AOU Senese, Siena, Italy.|Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), Siena, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Chiariello
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D004249:DNA Damage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013736:Testicular Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; D048049:Extracellular Signal-Regulated MAP Kinases; C456320:MAPK15 protein, human
keywords: DNA damage; MAP kinases; autophagy; embryonal carcinomas; p53