title: TRAP1-dependent regulation of p70S6K is involved in the attenuation of protein synthesis and cell migration: relevance in human colorectal tumors.
abstract: TNF receptor-associated protein 1 (TRAP1) is an HSP90 chaperone involved in stress protection and apoptosis in mitochondrial and extramitochondrial compartments. Remarkably, aberrant deregulation of TRAP1 function has been observed in several cancer types with potential new opportunities for therapeutic intervention in humans. Although previous studies by our group identified novel roles of TRAP1 in quality control of mitochondria-destined proteins through the attenuation of protein synthesis, molecular mechanisms are still largely unknown. To shed further light on the signaling pathways regulated by TRAP1 in the attenuation of protein synthesis, this study demonstrates that the entire pathway of cap-mediated translation is activated in cells following TRAP1 interference: consistently, expression and consequent phosphorylation of p70S6K and RSK1, two translation activating kinases, are increased upon TRAP1 silencing. Furthermore, we show that these regulatory functions affect the response to translational stress and cell migration in wound healing assays, processes involving both kinases. Notably, the regulatory mechanisms controlled by TRAP1 are conserved in colorectal cancer tissues, since an inverse correlation between TRAP1 and p70S6K expression is found in tumor tissues, thereby supporting the relevant role of TRAP1 translational regulation in vivo. Taken as a whole, these new findings candidate TRAP1 network for new anti-cancer strategies aimed at targeting the translational/quality control machinery of tumor cells.
authors: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors: Danilo Swann
authors: DS
authors: Matassa
authors: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors: Ilenia
authors: I
authors: Agliarulo
authors: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors: Maria Rosaria
authors: MR
authors: Amoroso
authors: Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors: Francesca
authors: F
authors: Maddalena
authors: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; Ceinge Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy.
authors: Leandra
authors: L
authors: Sepe
authors: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; Ceinge Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy.
authors: Maria Carla
authors: MC
authors: Ferrari
authors: Department of Biology, University of Rome 'Tor Vergata', Via Ricerca Scientifica, Rome 00133, Italy.
authors: Vinay
authors: V
authors: Sagar
authors: Department of Biology, University of Rome 'Tor Vergata', Via Ricerca Scientifica, Rome 00133, Italy.
authors: Silvia
authors: S
authors: D'Amico
authors: Department of Biology, University of Rome 'Tor Vergata', Via Ricerca Scientifica, Rome 00133, Italy.
authors: Fabrizio
authors: F
authors: Loreni
authors: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; Ceinge Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy.
authors: Giovanni
authors: G
authors: Paolella
authors: Clinical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors: Matteo
authors: M
authors: Landriscina
authors: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. Electronic address: franca.esposito@unina.it.
authors: Franca
authors: F
authors: Esposito
mesh_terms: D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D014176:Protein Biosynthesis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; C092306:TRAP1 protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa
keywords: Cell migration; Colorectal carcinoma; Ribavirin; TRAP1; Translation control; Wound healing