title: TRAP1 controls cell migration of cancer cells in metabolic stress conditions: Correlations with AKT/p70S6K pathways.
abstract: Cell motility is a highly dynamic phenomenon that is essential to physiological processes such as morphogenesis, wound healing and immune response, but also involved in pathological conditions such as metastatic dissemination of cancers. The involvement of the molecular chaperone TRAP1 in the regulation of cell motility, although still controversial, has been recently investigated along with some well-characterized roles in cancer cell survival and drug resistance in several tumour types. Among different functions, TRAP1-dependent regulation of protein synthesis seems to be involved in the migratory behaviour of cancer cells and, interestingly, the expression of p70S6K, a kinase responsible for translation initiation, playing a role in cell motility, is regulated by TRAP1. In this study, we demonstrate that TRAP1 silencing enhances cell motility in vitro but compromises the ability of cells to overcome stress conditions, and that this effect is mediated by the AKT/p70S6K pathway. In fact: i) inhibition of p70S6K activity specifically reduces migration in TRAP1 knock-down cells; ii) nutrient deprivation affects p70S6K activity thereby impairing cell migration only in TRAP1-deficient cells; iii) TRAP1 regulates the expression of both AKT and p70S6K at post-transcriptional level; and iii) TRAP1 silencing modulates the expression of genes involved in cell motility and epithelial-mesenchymal transition. Notably, a correlation between TRAP1 and AKT expression is found in vivo in human colorectal tumours. These results provide new insights into TRAP1 role in the regulation of cell migration in cancer cells, tumour progression and metastatic mechanisms.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Agliarulo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Danilo Swann
authors.initials: DS
authors.lastname: Matassa
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Amoroso
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Maddalena
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Sisinni
authors.affiliation: 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.forename: Leandra
authors.initials: L
authors.lastname: Sepe
authors.affiliation: 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.forename: Maria Carla
authors.initials: MC
authors.lastname: Ferrari
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Arzeni
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Avolio
authors.affiliation: 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.forename: Giovanni
authors.initials: G
authors.lastname: Paolella
authors.affiliation: Clinical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Landriscina
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Esposito
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D018841:HSP90 Heat-Shock Proteins; C092306:TRAP1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa
keywords: AKT/p70S6K pathway; Colorectal carcinoma; Metastasis; TRAP1; Wound healing