Prostate Cancer Discovery and Development Program

Philadelphia, PA, United States

Prostate Cancer Discovery and Development Program

Philadelphia, PA, United States
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Tavecchio M.,Prostate Cancer Discovery and Development Program | Lisanti S.,Prostate Cancer Discovery and Development Program | Lam A.,Prostate Cancer Discovery and Development Program | Ghosh J.C.,Prostate Cancer Discovery and Development Program | And 14 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Signals originated from mitochondria can affect other intracellular compartments. Results: Decreased levels in mitochondrial cyclophilin D promote cell proliferation and cell motility via chemokine/STAT3 signaling. Conclusion: Mitochondria regulate nuclear gene expression. Significance: Interorganelle signaling affects cell proliferation and cell motility. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Kang B.H.,Prostate Cancer Discovery and Development Program | Kang B.H.,Ulsan National Institute of Science and Technology | Tavecchio M.,Prostate Cancer Discovery and Development Program | Tavecchio M.,Wistar Institute | And 16 more authors.
British Journal of Cancer | Year: 2011

Background:The molecular chaperone heat shock protein-90 (Hsp90) is a promising cancer drug target, but current Hsp90-based therapy has so far shown limited activity in the clinic.Methods:We tested the efficacy of a novel mitochondrial-targeted, small-molecule Hsp90 inhibitor, Gamitrinib (GA mitochondrial matrix inhibitor), in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. The TRAMP mice receiving 3-week or 5-week systemic treatment with Gamitrinib were evaluated for localised or metastatic prostate cancer, prostatic intraepithelial neoplasia (PIN) or localised inflammation using magnetic resonance imaging, histology and immunohistochemistry. Treatment safety was assessed histologically in organs collected at the end of treatment. The effect of Gamitrinib on mitochondrial dysfunction was studied in RM1 cells isolated from TRAMP tumours.Results:Systemic administration of Gamitrinib to TRAMP mice inhibited the formation of localised prostate tumours of neuroendocrine or adenocarcinoma origin, as well as metastatic prostate cancer to abdominal lymph nodes and liver. The Gamitrinib treatment had no effect on PIN or prostatic inflammation, and caused no significant animal weight loss or organ toxicity. Mechanistically, Gamitrinib triggered acute mitochondrial dysfunction in RM1 cells, with loss of organelle inner membrane potential and release of cytochrome-c in the cytosol.Conclusions:The Gamitrinib has pre-clinical activity and favourable tolerability in a genetic model of localised and metastatic prostate cancer in immunocompetent mice. Selective targeting of mitochondrial Hsp90 could provide novel molecular therapy for patients with advanced prostate cancer. © 2011 Cancer Research UK. All rights reserved.


Altieri D.C.,Prostate Cancer Discovery and Development Program | Altieri D.C.,Wistar Institute | Stein G.S.,Prostate Cancer Discovery and Development Program | Stein G.S.,University of Massachusetts Medical School | And 4 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2012

Protein folding quality control does not occur randomly in cells, but requires the action of specialized molecular chaperones compartmentalized in subcellular microenvironments and organelles. Fresh experimental evidence has now linked a mitochondrial-specific Heat Shock Protein-90 (Hsp90) homolog, Tumor Necrosis Factor Receptor-Associated Protein-1 (TRAP-1) to pleiotropic signaling circuitries of organelle integrity and cellular homeostasis. TRAP-1-directed compartmentalized protein folding is broadly exploited in cancer and neurodegenerative diseases, presenting new opportunities for therapeutic intervention in humans. This article is part of a Special Issue entitled: Heat Shock Protein 90 (Hsp90). © 2011 Elsevier B.V.


Goel H.L.,University of Massachusetts Medical School | Sayeed A.,Prostate Cancer Discovery and Development Program | Sayeed A.,Thomas Jefferson University | Breen M.,University of Massachusetts Medical School | And 15 more authors.
Journal of Cellular Physiology | Year: 2013

This study was carried out to dissect the mechanism by which β1 integrins promote resistance to radiation. For this purpose, we conditionally ablated β1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to β1, AIIB2, in a xenograft model. The role of β1 integrins and of a β1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that β1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, β1 integrins are shown here to suppress activation of JNK1 and, consequently apoptosis, in response to irradiation. Downregulation of JNK1 is necessary to preserve the effect of β1 on resistance to radiation in vitro and in vivo. Finally, given the established crosstalk between β1 integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate β1 integrin levels. We report that IGF-IR regulates the expression of β1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that β1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation. © 2013 Wiley Periodicals, Inc..


PubMed | Thomas Jefferson University, University of Massachusetts Medical School and Prostate Cancer Discovery and Development Program
Type: | Journal: Oncotarget | Year: 2016

Radiation therapy is an effective cancer treatment modality although tumors invariably become resistant. Using the transgenic adenocarcinoma of mouse prostate (TRAMP) model system, we report that a hypofractionated radiation schedule (10 Gy/day for 5 consecutive days) effectively blocks prostate tumor growth in wild type (1wt /TRAMP) mice as well as in mice carrying a conditional ablation of 1 integrins in the prostatic epithelium (1pc-/- /TRAMP). Since JNK is known to be suppressed by 1 integrins and mediates radiation-induced apoptosis, we tested the effect of SP600125, an inhibitor of c-Jun amino-terminal kinase (JNK) in the TRAMP model system. Our results show that SP600125 negates the effect of radiation on tumor growth in 1pc-/- /TRAMP mice and leads to invasive adenocarcinoma. These effects are associated with increased focal adhesion kinase (FAK) expression and phosphorylation in prostate tumors in 1pc-/- /TRAMP mice. In marked contrast, radiation-induced tumor growth suppression, FAK expression and phosphorylation are not altered by SP600125 treatment of 1wt /TRAMP mice. Furthermore, we have reported earlier that abrogation of insulin-like growth factor receptor (IGF-IR) in prostate cancer cells enhances the sensitivity to radiation. Here we further explore the 1/IGF-IR crosstalk and report that 1 integrins promote cell proliferation partly by enhancing the expression of IGF-IR. In conclusion, we demonstrate that 1 integrin-mediated inhibition of JNK signaling modulates tumor growth rate upon hypofractionated radiation.


Leav I.,Prostate Cancer Discovery and Development Program | Plescia J.,Prostate Cancer Discovery and Development Program | Goel H.L.,Prostate Cancer Discovery and Development Program | Li J.,Prostate Cancer Discovery and Development Program | And 4 more authors.
American Journal of Pathology | Year: 2010

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 mitochondrialocalized 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. Copyright © American Society for Investigative Pathology.


Vaira V.,Prostate Cancer Discovery and Development Program | Faversani A.,Divisions of Pathology | Martin N.M.,Prostate Cancer Discovery and Development Program | Garlick D.S.,Prostate Cancer Discovery and Development Program | And 8 more authors.
Cancer Research | Year: 2013

Metastatic traits seem to be acquired by transformed cells with progenitor-like cancer-initiating properties, but there remains little mechanistic insight into this linkage. In this report, we show that the polarity protein Numbl, which is expressed normally in neuronal progenitors, becomes overexpressed and mislocalized in cancer cells from a variety of human tumors. Numbl overexpression relies on loss of the tumor suppressor miRNA-296-5p (miR-296), which actively represses translation of Numbl in normal cells. In turn, deregulated expression of Numbl mediates random tumor cell migration and invasion, blocking anoikis and promoting metastatic dissemination. In clinical specimens of non-small cell lung cancer, we found that Numbl overexpression correlated with a reduction in overall patient survival. Mechanistically, Numbl-mediated tumorigenesis involved suppression of a "stemness" transcriptional program driven by the stem cell programming transcription factor Klf4, thereby preserving a pool of progenitor-like cells in lung cancer. Our results reveal that Numbl-Klf4 signaling is critical to maintain multiple nodes of metastatic progression, including persistence of cancer-initiating cells, rationalizing its therapeutic exploitation to improve the treatment of advanced lung cancer. © 2013 American Association for Cancer Research.


Siegelin M.D.,Prostate Cancer Discovery and Development Program | Siegelin M.D.,Columbia University | Dohi T.,Prostate Cancer Discovery and Development Program | Dohi T.,Wistar Institute | And 8 more authors.
Journal of Clinical Investigation | Year: 2011

Fine tuning of the protein folding environment in subcellular organelles, such as mitochondria, is important for adaptive homeostasis and may participate in human diseases, but the regulators of this process are still largely elusive. Here, we have shown that selective targeting of heat shock protein-90 (Hsp90) chaperones in mitochondria of human tumor cells triggered compensatory autophagy and an organelle unfolded protein response (UPR) centered on upregulation of CCAAT enhancer binding protein (C/EBP) transcription factors. In turn, this transcriptional UPR repressed NF-κB-dependent gene expression, enhanced tumor cell apoptosis initiated by death receptor ligation, and inhibited intracranial glioblastoma growth in mice without detectable toxicity. These data reveal what we believe to be a novel role of Hsp90 chaperones in the regulation of the protein-folding environment in mitochondria of tumor cells. Disabling this general adaptive pathway could potentially be used in treatment of genetically heterogeneous human tumors.


PubMed | Prostate Cancer Discovery and Development Program
Type: Journal Article | Journal: Biochimica et biophysica acta | Year: 2012

Protein folding quality control does not occur randomly in cells, but requires the action of specialized molecular chaperones compartmentalized in subcellular microenvironments and organelles. Fresh experimental evidence has now linked a mitochondrial-specific Heat Shock Protein-90 (Hsp90) homolog, Tumor Necrosis Factor Receptor-Associated Protein-1 (TRAP-1) to pleiotropic signaling circuitries of organelle integrity and cellular homeostasis. TRAP-1-directed compartmentalized protein folding is broadly exploited in cancer and neurodegenerative diseases, presenting new opportunities for therapeutic intervention in humans. This article is part of a Special Issue entitled: Heat Shock Protein 90 (Hsp90).


PubMed | Prostate Cancer Discovery and Development Program
Type: Journal Article | Journal: British journal of cancer | Year: 2011

The molecular chaperone heat shock protein-90 (Hsp90) is a promising cancer drug target, but current Hsp90-based therapy has so far shown limited activity in the clinic.We tested the efficacy of a novel mitochondrial-targeted, small-molecule Hsp90 inhibitor, Gamitrinib (GA mitochondrial matrix inhibitor), in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. The TRAMP mice receiving 3-week or 5-week systemic treatment with Gamitrinib were evaluated for localised or metastatic prostate cancer, prostatic intraepithelial neoplasia (PIN) or localised inflammation using magnetic resonance imaging, histology and immunohistochemistry. Treatment safety was assessed histologically in organs collected at the end of treatment. The effect of Gamitrinib on mitochondrial dysfunction was studied in RM1 cells isolated from TRAMP tumours.Systemic administration of Gamitrinib to TRAMP mice inhibited the formation of localised prostate tumours of neuroendocrine or adenocarcinoma origin, as well as metastatic prostate cancer to abdominal lymph nodes and liver. The Gamitrinib treatment had no effect on PIN or prostatic inflammation, and caused no significant animal weight loss or organ toxicity. Mechanistically, Gamitrinib triggered acute mitochondrial dysfunction in RM1 cells, with loss of organelle inner membrane potential and release of cytochrome-c in the cytosol.The Gamitrinib has pre-clinical activity and favourable tolerability in a genetic model of localised and metastatic prostate cancer in immunocompetent mice. Selective targeting of mitochondrial Hsp90 could provide novel molecular therapy for patients with advanced prostate cancer.

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