Transgenic Expression of the Mitochondrial Chaperone TNFR-associated Protein 1 (TRAP1) Accelerates Prostate Cancer Development

Research output: Contribution to journalArticle

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.

Details

Authors
  • Sofia Lisanti
  • David S Garlick
  • Kelly G Bryant
  • Michele Tavecchio
  • Gordon B. Mills
  • Yiling Lu
  • Andrew V Kossenkov
  • Louise C Showe
  • Lucia R Languino
  • Dario C Altieri
External organisations
  • The Wistar Institute
Original languageEnglish
Pages (from-to)25247-25254
Number of pages8
JournalJournal of Biological Chemistry
Volume291
Issue number48
Publication statusPublished - 2016 Nov 25
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes