Cytoprotective Mitochondrial Chaperone TRAP-1 As a Novel Molecular Target in Localized and Metastatic Prostate Cancer

Abstract

Molecular chaperones of the heat shock protein-90 (Hsp90) family promote cell survival, but the molecular requirements of this pathway in tumor progression are not understood. Here, we show that a mitochondria-localized Hsp90 chaperone, tumor necrosis factor receptor-associated protein-1 (TRAP-1), is abundantly and ubiquitously expressed in human high-grade prostatic intraepithelial neoplasia, Gleason grades 3 through 5 prostatic adenocarcinomas, and metastatic prostate cancer, but largely undetectable in normal prostate or benign prostatic hyperplasia in vivo. Prostate lesions formed in genetic models of the disease, including the transgenic adenocarcinoma of the mouse prostate and mice carrying prostate-specific deletion of the phosphatase tensin homolog tumor suppressor (Pten(pc-/-)), also exhibit high levels of TRAP-1. Expression of TRAP-1 in nontransformed prostatic epithelial BPH-1 cells inhibited cell death, whereas silencing of TRAP-1 in androgen-independent PC3 or DU145 prostate cancer cells by small interfering RNA enhanced apoptosis. Targeting TRAP-1 with a novel class of mitochondria-directed Hsp90 inhibitors, ie, Gamitrinibs, caused rapid and complete killing of androgen-dependent or -independent prostate cancer, but not BPH-1 cells, whereas reintroduction of TRAP-1 in BPH-1 cells conferred sensitivity to Gamitrinib-induced cell death. These data identify TRAP-1 as a novel mitochondrial survival factor differentially expressed in localized and metastatic prostate cancer compared with normal prostate. Targeting this pathway with Gamitrinibs could be explored as novel molecular therapy in patients with advanced prostate cancer.

TRAP1 regulation of mitochondrial life or death decision in cancer cells and mitochondria-targeted TRAP1 inhibitors

“…Expression analysis with oligonucleotide microarrays revealed that TRAP1 is one of the target genes elevated by the Myc oncogene (38). TRAP1 was over-expressed in primary human fibroblasts and mouse prostate by SV40-induced malignant transformation (39,40). Various cancer cell lines, including mouse adenocarcinoma, and specimens from human cancer patients also consistently showed over-expression of TRAP1, while it remained undetectable in normal cells and tissues (16,40).…”

TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins

“…5 Little is known about TRAP1 signal transduction: the first most important finding on TRAP1 function came from studies by the Altieri's group, which identified TRAP1 as a member of a cytoprotective network selectively active in the mitochondria of tumor tissues. 6 The same group has recently proposed TRAP1 as a novel molecular target in localized and metastatic prostate cancer, 7 and is now involved in a promising preclinical characterization of mitochondria-targeted smallmolecule HSP90 inhibitors. 8,9 Besides some well-characterized TRAP1 functions in mitochondria, during preparation of this manuscript it was reported that interference by HSP90 chaperones triggers an unfolded protein response (UPR) and activates autophagy in the mitochondria of tumor cells.…”

Prostate Cancer

“…10,11 Loss of cancer suppressor genes localized to chromosome 8p,10q,13q, 16q are sen in early prostatic carcinogenesis.p53 mutation in primary prostate cancer is low and more frequently seen in metastatic carcinoma hence p53 mutation is a late event in prostate cancer. Loss of PTEN gene and KAI gene are also important in prostatic cancer.About 70% of men with prostate cancer lost PTEN gene at the time of diagnosis.Loss of ecadherin and CD44 have also being observed 15 . RUNX2 is a transcription factor that prevents cancer cells undergoing apoptosis and also contribute to development of Prostate carcinoma.…”

“…PTEN gene at the time of diagnosis.Loss of ecadherin and CD44 have also being observed 15 . RUNX2 is a transcription factor that prevents cancer cells undergoing apoptosis and also contribute to development of Prostate carcinoma.…”

“…Higher meat consumption has been associated with a higher risk in some studies. Lower blood levels of vitamin D may increase the risk of developing prostate cancer 15 . Folic acid supplements have no effect on the risk of developing prostate cancer 16 .…”