title: TRAP1 is involved in BRAF regulation and downstream attenuation of ERK phosphorylation and cell-cycle progression: a novel target for BRAF-mutated colorectal tumors.
abstract: Human BRAF-driven tumors are aggressive malignancies with poor clinical outcome and lack of sensitivity to therapies. TRAP1 is a HSP90 molecular chaperone deregulated in human tumors and responsible for specific features of cancer cells, i.e., protection from apoptosis, drug resistance, metabolic regulation, and protein quality control/ubiquitination. The hypothesis that TRAP1 plays a regulatory function on the BRAF pathway, arising from the observation that BRAF levels are decreased upon TRAP1 interference, was tested in human breast and colorectal carcinoma in vitro and in vivo. This study shows that TRAP1 is involved in the regulation of BRAF synthesis/ubiquitination, without affecting its stability. Indeed, BRAF synthesis is facilitated in a TRAP1-rich background, whereas increased ubiquitination occurs upon disruption of the TRAP1 network that correlates with decreased protein levels. Remarkably, BRAF downstream pathway is modulated by TRAP1 regulatory activity: indeed, TRAP1 silencing induces (i) ERK phosphorylation attenuation, (ii) cell-cycle inhibition with cell accumulation in G0-G1 and G2-M transitions, and (iii) extensive reprogramming of gene expression. Interestingly, a genome-wide profiling of TRAP1-knockdown cells identified cell growth and cell-cycle regulation as the most significant biofunctions controlled by the TRAP1 network. It is worth noting that TRAP1 regulation on BRAF is conserved in human colorectal carcinomas, with the two proteins being frequently coexpressed. Finally, the dual HSP90/TRAP1 inhibitor HSP990 showed activity against the TRAP1 network and high cytostatic potential in BRAF-mutated colorectal carcinoma cells. Therefore, this novel TRAP1 function represents an attractive therapeutic window to target dependency of BRAF-driven tumors on TRAP1 translational/quality control machinery.
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Condelli
authors.affiliation: Clinical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Piscazzi
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, 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.
authors.forename: Danilo Swann
authors.initials: DS
authors.lastname: Matassa
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, 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, Potenza, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Lettini
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Simeon
authors.affiliation: Clinical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palladino
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. 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, Potenza, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Trino
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. matteo.landriscina@unifg.it franca.esposito@unina.it.
authors.forename: Franca
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Clinical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. matteo.landriscina@unifg.it franca.esposito@unina.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Landriscina
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000502:physiology; D054875:Ubiquitination
chemical_list: D018841:HSP90 Heat-Shock Proteins; C092306:TRAP1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases