title: Transgenic Expression of the Mitochondrial Chaperone TNFR-associated Protein 1 (TRAP1) Accelerates Prostate Cancer Development.
abstract: Protein homeostasis, or proteostasis, is required for mitochondrial function, but its role in cancer is controversial. Here we show that transgenic mice expressing the mitochondrial chaperone TNFR-associated protein 1 (TRAP1) in the prostate develop epithelial hyperplasia and cellular atypia. When examined on a Pten+/-background, a common alteration in human prostate cancer, TRAP1 transgenic mice showed accelerated incidence of invasive prostatic adenocarcinoma, characterized by increased cell proliferation and reduced apoptosis, in situ Conversely, homozygous deletion of TRAP1 delays prostatic tumorigenesis in Pten+/-mice without affecting hyperplasia or prostatic intraepithelial neoplasia. Global profiling of Pten+/--TRAP1 transgenic mice by RNA sequencing and reverse phase protein array reveals modulation of oncogenic networks of cell proliferation, apoptosis, cell motility, and DNA damage. Mechanistically, reconstitution of Pten+/-prostatic epithelial cells with TRAP1 increases cell proliferation, reduces apoptosis, and promotes cell invasion without changes in mitochondrial bioenergetics. Therefore, TRAP1 is a driver of prostate cancer in vivo and an "actionable" therapeutic target.
authors.affiliation: From the Prostate Cancer Discovery and Development Program.|Tumor Microenvironment and Metastasis Program.
authors.forename: Sofia
authors.initials: S
authors.lastname: Lisanti
authors.affiliation: From the Prostate Cancer Discovery and Development Program.
authors.forename: David S
authors.initials: DS
authors.lastname: Garlick
authors.affiliation: From the Prostate Cancer Discovery and Development Program.|Tumor Microenvironment and Metastasis Program.
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Bryant
authors.affiliation: From the Prostate Cancer Discovery and Development Program.|Tumor Microenvironment and Metastasis Program.
authors.forename: Michele
authors.initials: M
authors.lastname: Tavecchio
authors.affiliation: the Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, and.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: the Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, and.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Center for Systems and Computational Biology, and.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.affiliation: Center for Systems and Computational Biology, and.|Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Showe
authors.affiliation: From the Prostate Cancer Discovery and Development Program.|the Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
authors.affiliation: From the Prostate Cancer Discovery and Development Program, daltieri@wistar.org.|Tumor Microenvironment and Metastasis Program.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D018841:HSP90 Heat-Shock Proteins; D009363:Neoplasm Proteins; C547760:TRAP-1 protein, mouse; C092306:TRAP1 protein, human
keywords: chaperone; heat shock protein 90 (Hsp90); mitochondria; prostate cancer; protein folding