Transgenic expression of the mitochondrial chaperone TNFR-associated protein 1 (TRAP1) accelerates prostate cancer development

Sofia Lisanti, David S. Garlick, Kelly G. Bryant, Michele Tavecchio, Gordon Mills, Yiling Lu, Andrew V. Kossenkov, Louise C. Showe, Lucia R. Languino, Dario C. Altieri

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)25247-25254
Number of pages8
JournalJournal of Biological Chemistry
Volume291
Issue number48
DOIs
StatePublished - Nov 25 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Lisanti, S., Garlick, D. S., Bryant, K. G., Tavecchio, M., Mills, G., Lu, Y., Kossenkov, A. V., Showe, L. C., Languino, L. R., & Altieri, D. C. (2016). Transgenic expression of the mitochondrial chaperone TNFR-associated protein 1 (TRAP1) accelerates prostate cancer development. Journal of Biological Chemistry, 291(48), 25247-25254. https://doi.org/10.1074/jbc.M116.745950