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

Lisanti, Sofia; Garlick, David S; Bryant, Kelly G; Tavecchio, Michele LU ; Mills, Gordon B.; Lu, Yiling; Kossenkov, Andrew V; Showe, Louise C; Languino, Lucia R and Altieri, Dario C (2016) In Journal of Biological Chemistry 291(48). p.25247-25254
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... (More)

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.

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author
publishing date
type
Contribution to journal
publication status
published
in
Journal of Biological Chemistry
volume
291
issue
48
pages
8 pages
publisher
ASBMB
external identifiers
  • scopus:84997585147
ISSN
1083-351X
DOI
10.1074/jbc.M116.745950
language
English
LU publication?
no
id
8ab372ab-5135-475e-859d-58a1a1d755d2
date added to LUP
2017-03-07 09:02:31
date last changed
2017-08-06 05:18:50
@article{8ab372ab-5135-475e-859d-58a1a1d755d2,
  abstract     = {<p>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.</p>},
  author       = {Lisanti, Sofia and Garlick, David S and Bryant, Kelly G and Tavecchio, Michele and Mills, Gordon B. and Lu, Yiling and Kossenkov, Andrew V and Showe, Louise C and Languino, Lucia R and Altieri, Dario C},
  issn         = {1083-351X},
  language     = {eng},
  month        = {11},
  number       = {48},
  pages        = {25247--25254},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Transgenic Expression of the Mitochondrial Chaperone TNFR-associated Protein 1 (TRAP1) Accelerates Prostate Cancer Development},
  url          = {http://dx.doi.org/10.1074/jbc.M116.745950},
  volume       = {291},
  year         = {2016},
}