TY - JOUR
T1 - Transgenic expression of the mitochondrial chaperone TNFR-associated protein 1 (TRAP1) accelerates prostate cancer development
AU - Lisanti, Sofia
AU - Garlick, David S.
AU - Bryant, Kelly G.
AU - Tavecchio, Michele
AU - Mills, Gordon B.
AU - Lu, Yiling
AU - Kossenkov, Andrew V.
AU - Showe, Louise C.
AU - Languino, Lucia R.
AU - Altieri, Dario C.
N1 - Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/11/25
Y1 - 2016/11/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84997585147&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84997585147&partnerID=8YFLogxK
U2 - 10.1074/jbc.M116.745950
DO - 10.1074/jbc.M116.745950
M3 - Article
C2 - 27754870
AN - SCOPUS:84997585147
SN - 0021-9258
VL - 291
SP - 25247
EP - 25254
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 48
ER -