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J Biol Chem. 2016 Nov 25;291(48):25247-25254. Epub 2016 Oct 17.

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

Author information

1
From the Prostate Cancer Discovery and Development Program.
2
Tumor Microenvironment and Metastasis Program.
3
the Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, and.
4
Center for Systems and Computational Biology, and.
5
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104.
6
the Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
7
From the Prostate Cancer Discovery and Development Program, daltieri@wistar.org.

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.

KEYWORDS:

chaperone; heat shock protein 90 (Hsp90); mitochondria; prostate cancer; protein folding

PMID:
27754870
PMCID:
PMC5122790
DOI:
10.1074/jbc.M116.745950
[Indexed for MEDLINE]
Free PMC Article

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