Metallothionein & Cadmium Carcinogenesis in the Prostate

Summary

Principal Investigator: Shuk Mei Ho
Abstract: [unreadable] DESCRIPTION (provided by applicant): Cadmium (Cd) is a significant and growing environmental contaminant. Cd exposure has been linked to prostate cancer (PCa) in some, but not all epidemiological studies. In rats, Cd is a proven carcinogen of the prostate. Although little is known about the mechanisms of Cd-carcinogenicity, several lines of evidence point to an involvement of metallothioneins (MTs), a family of Cd-copper-zinc binding proteins in the process. During our last funding period, we have made several major contributions to the field of Cd and metallothionein research: a) We have developed highly sensitive, sequence-specific quantitative RT-PCR protocols for rodent MT-I and MT-Il quantification and demonstrated that, despite of their low expression, MT-I and -Il genes are inducible in rat ventral prostate, b) We have generated the first ribozymes (Rzs) which can induce sequence-specific degradation of rat and mouse MT-I and MT-lI mRNA, respectively. Significantly, sequence analyzes predict that these Rzs Will degrade many human MTs. Cell transfection studies demonstrated that MT Rzs work effectively in cellulo and degradation of MT mRNA increases cellular susceptibility to Cd cytotoxicity, c) Importantly, transgenic expression of MT Rzs in human prostatic cancer cell lines induces a dramatic apoptotic response, suggesting that MTs are cell survival factors and MT Rzs potent anticancer agents, and d) We have generated a prostate-specific, MT-I overexpresser using a third generation probasin (PB) promoter, ARR2, to target MT-1 expression. This animal, referred as PBMT-1, exhibits intra-epithelial atypia beginning at 26-week of age and widespread prostatic dysplasia by 56-week of age. Based on these findings we now hypothesize that overexpression of MT in prostatic epithelial cells increases cell survival and favors accumulation of premalignant and early malignant cells. Hence, we predict that the PBMT-1 transgenic animal will be more susceptible to Cd-induced neoplastic tansformation. Our recent preliminary findings support this premise since we found widespread dysplasia developed in the VPs of PBMT-1 within 96 hours after a single dose of CdCl2 injection. Furthermore, we predict Rz-mediated degradation of MT-I mRNA will reverse dysplasia/neoplasia development in PBMT-1. These hypotheses will be tested in vivo. Aim 1: To determine whether PBMT-1 mice are more/less susceptible to Cd-induced cytotoxicity/carcinogenicity. Aim 2: Part-1 Human adenovirus vectors (AdV) will be used to deliver MT Rz to PBMT-I, via an orthotopic route, to determine if down-regulation of MT-1 mRNA levels will reverse the development of dysplasia/neoplasia in its prostates Part-2 By cross-breeding with a mouse, named CAR, which expresses membrane Coxsackie/human Adenovirus Receptors (hCAR) on all body cells, with PBMT-1 we will generated the CAR/PBMT-1 mouse. We will then test whether expression of hCAR on murine cells will enhance hAdV-mediated delivery of MT Rz to murine prostatic cells and increase Rz efficacy. These studies are expected to advance our understanding of the relationship between MTs and Cd-cytotoxicity/carcinogencity, generate new preclinical models for future development of gene therapy protocols based on the MT Rz technology.
Funding Period: 1995-07-01 - 2009-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Differential attenuation of oxidative/nitrosative injuries in early prostatic neoplastic lesions in TRAMP mice by dietary antioxidants
    Neville N C Tam
    Department of Surgery, Division of Urology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    Prostate 66:57-69. 2006
  2. pmc Ribosome-inactivating proteins isolated from dietary bitter melon induce apoptosis and inhibit histone deacetylase-1 selectively in premalignant and malignant prostate cancer cells
    Su Dao Xiong
    Institute of Hematology and Tumor Biology Research, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
    Int J Cancer 125:774-82. 2009
  3. pmc Estrogens and prostate cancer: etiology, mediators, prevention, and management
    Shuk Mei Ho
    Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
    Endocrinol Metab Clin North Am 40:591-614, ix. 2011
  4. pmc Site-specific S-nitrosylation of integrin α6 increases the extent of prostate cancer cell migration by enhancing integrin β1 association and weakening adherence to laminin-1
    Jared Isaac
    Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    Biochemistry 51:9689-97. 2012
  5. pmc Sex hormones induce direct epithelial and inflammation-mediated oxidative/nitrosative stress that favors prostatic carcinogenesis in the noble rat
    Neville N C Tam
    Department of Environmental Health, Kettering Complex, Room 130, 3223 Eden Ave, University of Cincinnati Medical Center, PO Box 670056, Cincinnati, OH 45267 0056, USA
    Am J Pathol 171:1334-41. 2007
  6. pmc Transcriptome analyses in normal prostate epithelial cells exposed to low-dose cadmium: oncogenic and immunomodulations involving the action of tumor necrosis factor
    Shlomo Bakshi
    Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 0056, USA
    Environ Health Perspect 116:769-76. 2008
  7. pmc Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer
    M J Schiewer
    Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Oncogene 28:1016-27. 2009
  8. pmc Deletion hotspots in AMACR promoter CpG island are cis-regulatory elements controlling the gene expression in the colon
    Xiang Zhang
    Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    PLoS Genet 5:e1000334. 2009
  9. pmc Comprehensive identification and modified-site mapping of S-nitrosylated targets in prostate epithelial cells
    Ying Wai Lam
    Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
    PLoS ONE 5:e9075. 2010

Scientific Experts

  • Shuk Mei Ho
  • Karen Knudsen
  • Ying Wai Lam
  • Xiang Zhang
  • Neville N C Tam
  • Jared Isaac
  • Shlomo Bakshi
  • Yong Yuan
  • M J Schiewer
  • Su Dao Xiong
  • Mario Medvedovic
  • Irwin Leav
  • Pheruza Tarapore
  • C V Suresh Babu
  • Jarek Meller
  • L M Morey
  • Zhong Jiang
  • Jian Buo Wu
  • Kang Yu
  • Analisa Difeo
  • Shen Yao
  • C J Burd
  • Li Hui Yin
  • Goutham Narla
  • Alice C Levine
  • D E Merry
  • Ranjan Deka
  • Monica P Revelo
  • Alexander Kirschenbaum
  • Xin Hua Liu
  • Y Liu
  • Robert Yuk Sing Cheng
  • Maureen A Sartor
  • Sonia Godoy-Tundidor
  • Robert R Maronpot
  • Margalit Bergman
  • Liat Lomnitski
  • Andrew Suttie
  • Shlomo Grossman
  • Abraham Nyska
  • Grace Kissling

Detail Information

Publications9

  1. ncbi Differential attenuation of oxidative/nitrosative injuries in early prostatic neoplastic lesions in TRAMP mice by dietary antioxidants
    Neville N C Tam
    Department of Surgery, Division of Urology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    Prostate 66:57-69. 2006
    ..Experimental evidence establishing a causal relationship between oxidative and nitrosative stress (OS/NS) and PCa development and showing its modulation by dietary antioxidants would help justify their usage...
  2. pmc Ribosome-inactivating proteins isolated from dietary bitter melon induce apoptosis and inhibit histone deacetylase-1 selectively in premalignant and malignant prostate cancer cells
    Su Dao Xiong
    Institute of Hematology and Tumor Biology Research, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
    Int J Cancer 125:774-82. 2009
    ..These results suggest that Type I RIPs derived from plants are HDAC inhibitors that can be utilized in the prevention and treatment of prostate cancer...
  3. pmc Estrogens and prostate cancer: etiology, mediators, prevention, and management
    Shuk Mei Ho
    Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
    Endocrinol Metab Clin North Am 40:591-614, ix. 2011
    ....
  4. pmc Site-specific S-nitrosylation of integrin α6 increases the extent of prostate cancer cell migration by enhancing integrin β1 association and weakening adherence to laminin-1
    Jared Isaac
    Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    Biochemistry 51:9689-97. 2012
    ..In conclusion, S-nitrosylation of ITGα6 increased the extent of prostate cancer cell migration, which could be a potential mechanism of NO- and iNOS-induced enhancement of prostate cancer metastasis...
  5. pmc Sex hormones induce direct epithelial and inflammation-mediated oxidative/nitrosative stress that favors prostatic carcinogenesis in the noble rat
    Neville N C Tam
    Department of Environmental Health, Kettering Complex, Room 130, 3223 Eden Ave, University of Cincinnati Medical Center, PO Box 670056, Cincinnati, OH 45267 0056, USA
    Am J Pathol 171:1334-41. 2007
    ..Thus, we link alterations in the hormonal milieu with oxidative/nitrosative/inflammatory damage to the prostate epithelium that promotes carcinogenesis...
  6. pmc Transcriptome analyses in normal prostate epithelial cells exposed to low-dose cadmium: oncogenic and immunomodulations involving the action of tumor necrosis factor
    Shlomo Bakshi
    Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 0056, USA
    Environ Health Perspect 116:769-76. 2008
    ..Cadmium is implicated in prostate carcinogenesis, but its oncogenic action remains unclear...
  7. pmc Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer
    M J Schiewer
    Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Oncogene 28:1016-27. 2009
    ....
  8. pmc Deletion hotspots in AMACR promoter CpG island are cis-regulatory elements controlling the gene expression in the colon
    Xiang Zhang
    Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    PLoS Genet 5:e1000334. 2009
    ..Our findings identified key in vivo events and novel transcription factors responsible for AMACR regulation in CCas and suggested these AMACR deletions may have diagnostic/prognostic value for colon carcinogenesis...
  9. pmc Comprehensive identification and modified-site mapping of S-nitrosylated targets in prostate epithelial cells
    Ying Wai Lam
    Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
    PLoS ONE 5:e9075. 2010
    ..Thus, our primary objective was to identify S-nitrosylated targets in an immortalized normal prostate epithelial cell line, NPrEC...