delta-Catenin and Cell-Cell Adhesion in Prostate Cancer

Summary

Principal Investigator: Qun Lu
Abstract: Prostate cancer (CaP) is the most common malignancy in men in US and the second leading cause of cancer mortality. To reduce the significant morbidity and mortality, new strategies for CaP prevention and treatment depend on the determination of specific molecular mechanisms involved in this disease. 8-Catenin is a unique armadillo (ARM)domain-containing protein in that it is neural specific and primarily expresses in the brain. However, 8-catenin expression increases in prostatic adenocarcinomas, redistributes E-cadherin/120ctn from the cell-cell junction, and promotes CaP cell growth and invasion. To investigate this largely unexplored area of neuronal catenin gene expression in peripheral tissues of cancers, the overall goal of this project is to test the hypothesis that 8-catenin promotes CaP formation and progression by interacting with multiple cellular machineries, including cell-cell and cell-matrix adhesion, cell growth/survival, and invasion. There are three specific aims in this proposal. Specific Aim 1 will determine how 8-catenin promotes cell growth/survival and motility in response to the hepatocyte growth factor and/or androgen using CWR22 tumor xenografts and their derived cell lines. We will broadly screen and profile the S-catenin induced alteration of signaling molecules by array technology. These studies will identify cancer specific pathways that 8-catenin is involved in and will investigate their interactions with S-catenin using protein co-immunoprecipitation and yeast two-hybrid analyses. Specific Aim 2 will determine how 8-catenin interacts with Rho family small GTPases to disrupt adherens junction and promote CaP cell growth/survival and invasion. We will first identify the 8-catenin sequence responsible for this action. Then, the analyses of 8-catenin RNAi or its mutants that are defective in Rac-1 or E-cadherin binding will determine the interactions between GTP-Rac-1/IQGAP-1 and E-cadherin/p120ctn pathways to reveal possible differential modulations on cell-cell adhesion and cell growth/survival and invasion. We will also determine the cytoplasmic accumulation and nuclear signaling of (3-catenin that is released from E- cadherin complexes by IQGAP-1. Specific Aim 3 will apply Y311, a unique (dePhospho-specific) monoclonal antibody, and site-directed mutagenesis to determine how 8-catenin modifications occur and what are their roles in CaP. We will also investigate S-catenin proteolytic fragments and their potentials as DNA binding proteins and nuclear signaling for gene expression. Finally, we will generate transgenic mice displaying prostate tissue specific S-catenin expression to approach these questions at the animal level. These studies will place 8-catenin into the broad context of growth factor and kinase signaling machineries relevant to CaP. Understanding the posttranslational modifications that control 8-catenin functions will unravel mechanisms by which S-catenin modulates gene expression and promotes CaP in vivo.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Referenceless MR thermometry for monitoring thermal ablation in the prostate
    Viola Rieke
    Radiological Sciences Laboratory, Department of Radiology, Stanford University, Stanford, CA 94305, USA
    IEEE Trans Med Imaging 26:813-21. 2007
  2. pmc C-Src-mediated phosphorylation of δ-catenin increases its protein stability and the ability of inducing nuclear distribution of β-catenin
    Yongfeng He
    College of Pharmacy, Research Institute for Drug Development, Chonnam National University, Gwangju, South Korea
    Biochim Biophys Acta 1843:758-68. 2014
  3. pmc Small molecule targeting Cdc42-intersectin interaction disrupts Golgi organization and suppresses cell motility
    Amy Friesland
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
    Proc Natl Acad Sci U S A 110:1261-6. 2013
  4. pmc Human homolog of Drosophila Hairy and enhancer of split 1, Hes1, negatively regulates δ-catenin (CTNND2) expression in cooperation with E2F1 in prostate cancer
    Jian Ping Lu
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
    Mol Cancer 9:304. 2010
  5. pmc Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment
    Tao Yang
    Department of Neurology and Neurological Science, Stanford University, Stanford, California, USA
    PLoS ONE 3:e3604. 2008
  6. pmc Delta-catenin-induced dendritic morphogenesis. An essential role of p190RhoGEF interaction through Akt1-mediated phosphorylation
    Hangun Kim
    College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500 757, Korea
    J Biol Chem 283:977-87. 2008
  7. pmc Echo combination to reduce proton resonance frequency (PRF) thermometry errors from fat
    Viola Rieke
    Department of Radiology, Stanford University, Stanford, CA 94305 5488, USA
    J Magn Reson Imaging 27:673-7. 2008
  8. pmc Identification of E2F1 as a positive transcriptional regulator for delta-catenin
    Kwonseop Kim
    Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, 600 Moye Street, Greenville, NC 27834, USA
    Biochem Biophys Res Commun 369:414-20. 2008
  9. pmc Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants
    Sarah E James
    Department of Anatomy and Cell Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States
    Neurotoxicology 29:605-12. 2008
  10. pmc E-Cadherin negatively modulates delta-catenin-induced morphological changes and RhoA activity reduction by competing with p190RhoGEF for delta-catenin
    Hangun Kim
    College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Bldg 1 211, 300 Yongbong Dong, Gwangju 500 757, Republic of Korea
    Biochem Biophys Res Commun 377:636-41. 2008

Scientific Experts

  • Qun Lu
  • Yan Zeng
  • Kwonseop Kim
  • Hangun Kim
  • Sarah E James
  • Jiao Zhang
  • Minsoo Oh
  • Ilhwan Yang
  • Sonja Bareiss
  • Viola Rieke
  • Yongfeng He
  • Yan Hua Chen
  • Jian Ping Lu
  • Hyunkyoung Ki
  • Tao Yang
  • Amy Friesland
  • Dong Deuk Kwon
  • Jae Hyuk Lee
  • C Boykin
  • Kwang Youl Lee
  • Y H Chen
  • T Wang
  • Dongmin Gu
  • Mayisha W Dunham
  • M Elizabeth Fini
  • Youmei Xie
  • Frank M Longo
  • Stephen M Massa
  • Kim Butts Pauly
  • Won Seok Choi
  • Kyeong Man Kim
  • Yechan Joh
  • Mei Zheng
  • Taeyong Ryu
  • Huchen Zhou
  • Lie Wang
  • Yaxue Zhao
  • Yonghee Kim
  • Jeong Joon Min
  • Mary Jo Murnane
  • Young Woo Seo
  • Chaeyong Jung
  • Kyung Keun Kim
  • G Zhang
  • W M Yang
  • R W Zhang
  • X E Fan
  • Michael Wolfe
  • Mayisha Dunham
  • Jongdee Nopparat
  • Baoan Chen
  • Monica Carrion-Jones
  • Ockyoung Chang
  • Thomas C Case
  • Alexander Murashov
  • Robert J Matusik
  • Karl Heinz Krause
  • David M Suter
  • Wei Tao Cong
  • B Jeansonne
  • H Hong
  • Pierre D McCrea
  • Sabrina A Stratton
  • Moon Chang Baek
  • J Zhang
  • Inho Kwon
  • Jinhyung No
  • Amy K Sater
  • Melissa Clark
  • Hong Ji
  • Kyucheol Cho
  • Ja Hye Park
  • Michelle C Barton
  • Teresa E Lever
  • J P Lu
  • Jung Kap Choi
  • Monica J Carrion-Jones
  • Sunghoe Chang
  • Laura A Moore
  • Hubert Burden
  • Tao Wang
  • Hong Zhang
  • Jayakumar Rajadas
  • Timothy Chang
  • Gerald G Fuller
  • Woo Joo Song
  • Katrin Andreasson
  • JULIET K KNOWLES
  • Dawei Li
  • Jeong Ran Han

Detail Information

Publications28

  1. pmc Referenceless MR thermometry for monitoring thermal ablation in the prostate
    Viola Rieke
    Radiological Sciences Laboratory, Department of Radiology, Stanford University, Stanford, CA 94305, USA
    IEEE Trans Med Imaging 26:813-21. 2007
    ..The method is demonstrated feasibile in phantoms and during in vivo thermal ablation of canine prostate...
  2. pmc C-Src-mediated phosphorylation of δ-catenin increases its protein stability and the ability of inducing nuclear distribution of β-catenin
    Yongfeng He
    College of Pharmacy, Research Institute for Drug Development, Chonnam National University, Gwangju, South Korea
    Biochim Biophys Acta 1843:758-68. 2014
    ..Taken together, these results indicate that c-Src can enhance the oncogenic function of δ-catenin in prostate cancer cells. ..
  3. pmc Small molecule targeting Cdc42-intersectin interaction disrupts Golgi organization and suppresses cell motility
    Amy Friesland
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
    Proc Natl Acad Sci U S A 110:1261-6. 2013
    ....
  4. pmc Human homolog of Drosophila Hairy and enhancer of split 1, Hes1, negatively regulates δ-catenin (CTNND2) expression in cooperation with E2F1 in prostate cancer
    Jian Ping Lu
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
    Mol Cancer 9:304. 2010
    ....
  5. pmc Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment
    Tao Yang
    Department of Neurology and Neurological Science, Stanford University, Stanford, California, USA
    PLoS ONE 3:e3604. 2008
    ....
  6. pmc Delta-catenin-induced dendritic morphogenesis. An essential role of p190RhoGEF interaction through Akt1-mediated phosphorylation
    Hangun Kim
    College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500 757, Korea
    J Biol Chem 283:977-87. 2008
    ..These results highlight signaling events in the regulation of delta-catenin-induced dendrogenesis and spine morphogenesis...
  7. pmc Echo combination to reduce proton resonance frequency (PRF) thermometry errors from fat
    Viola Rieke
    Department of Radiology, Stanford University, Stanford, CA 94305 5488, USA
    J Magn Reson Imaging 27:673-7. 2008
    ..To validate echo combination as a means to reduce errors caused by fat in temperature measurements with the proton resonance frequency (PRF) shift method...
  8. pmc Identification of E2F1 as a positive transcriptional regulator for delta-catenin
    Kwonseop Kim
    Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, 600 Moye Street, Greenville, NC 27834, USA
    Biochem Biophys Res Commun 369:414-20. 2008
    ....
  9. pmc Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants
    Sarah E James
    Department of Anatomy and Cell Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States
    Neurotoxicology 29:605-12. 2008
    ..Therefore, the neurotoxicity resulting from exposure to the anti-cancer drugs cisplatin and methotrexate can be alleviated by inhibiting Rho signaling pathway...
  10. pmc E-Cadherin negatively modulates delta-catenin-induced morphological changes and RhoA activity reduction by competing with p190RhoGEF for delta-catenin
    Hangun Kim
    College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Bldg 1 211, 300 Yongbong Dong, Gwangju 500 757, Republic of Korea
    Biochem Biophys Res Commun 377:636-41. 2008
    ..These results suggest that delta-catenin is more dominantly bound to E-cadherin than to p190RhoGEF, and that delta-catenin's function is dependent on its cellular binding partner...
  11. pmc Increased nucleotide polymorphic changes in the 5'-untranslated region of delta-catenin (CTNND2) gene in prostate cancer
    T Wang
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
    Oncogene 28:555-64. 2009
    ..This is the first report of delta-catenin gene mutation in cancer and supports the notion that multiple mechanisms contribute to its increased expression in carcinogenesis...
  12. pmc δ-Catenin dysregulation in cancer: interactions with E-cadherin and beyond
    Qun Lu
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
    J Pathol 222:119-23. 2010
    ..Looking towards the future, the understanding of delta-catenin and p120(ctn) with and beyond their localization at the cell-cell junction should provide further insight into their roles in cancer pathogenesis...
  13. pmc Alzheimer's disease-linked presenilin mutation (PS1M146L) induces filamin expression and γ-secretase independent redistribution
    Qun Lu
    Harriet and John Wooten Laboratory for Alzheimer s Disease and Neurodegenerative Diseases Research, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
    J Alzheimers Dis 22:235-45. 2010
    ..These studies support a γ-secretase-independent role of PS1 in modulation of filamin-mediated actin cytoskeleton...
  14. pmc Cucurbitacin IIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation
    C Boykin
    Department of Anatomy and Cell Biology, East Carolina University, Greenville, NC 27834, USA
    Br J Cancer 104:781-9. 2011
    ..Recently, inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling was shown to underlie the effects of Cuc family on inducing cell death in cancer...
  15. pmc δ-Catenin promotes E-cadherin processing and activates β-catenin-mediated signaling: implications on human prostate cancer progression
    Hangun Kim
    College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, Republic of Korea
    Biochim Biophys Acta 1822:509-21. 2012
    ..Taken together, these results suggest that δ-catenin plays an important role in prostate cancer progression through inducing E-cadherin processing and thereby activating β-catenin-mediated oncogenic signals...
  16. pmc Delta-catenin/NPRAP: A new member of the glycogen synthase kinase-3beta signaling complex that promotes beta-catenin turnover in neurons
    Sonja Bareiss
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA
    J Neurosci Res 88:2350-63. 2010
    ....
  17. pmc Pro-oncogenic and anti-oncogenic pathways: opportunities and challenges of cancer therapy
    Jiao Zhang
    Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
    Future Oncol 6:587-603. 2010
    ..We propose future oncology interventions with the concept of integrative cancer therapy...
  18. pmc Identification of extracellular delta-catenin accumulation for prostate cancer detection
    Qun Lu
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA
    Prostate 69:411-8. 2009
    ..In this study, we investigated the hypothesis of delta-catenin accumulation in the urine of prostate cancer patients and its potential pathways of excretion into extracellular milieu...
  19. pmc delta-Catenin promotes prostate cancer cell growth and progression by altering cell cycle and survival gene profiles
    Yan Zeng
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA
    Mol Cancer 8:19. 2009
    ..We hypothesized that delta-catenin plays a direct role in prostate cancer progression by altering gene profiles of cell cycle regulation and cell survival...
  20. pmc Methodology to obtain a mixed sural nerve recording in mice
    Mayisha W Dunham
    Department of Physical Medicine and Rehabilitation, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27834, USA
    Am J Phys Med Rehabil 88:542-6. 2009
    ..Studying transgenic mice with various pathologies adds to our knowledge of the natural history of a disease. It is imperative, however, to compare disease models with the appropriate control...
  21. pmc Signaling through Rho GTPase pathway as viable drug target
    Qun Lu
    Department of Anatomy, East Carolina University, The Brody School of Medicine, 600 Moye Boulevard, Greenville, NC 27834, USA
    Curr Med Chem 16:1355-65. 2009
    ....
  22. pmc GSK-3 phosphorylates delta-catenin and negatively regulates its stability via ubiquitination/proteosome-mediated proteolysis
    Minsoo Oh
    College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500 757, Korea
    J Biol Chem 284:28579-89. 2009
    ..These results suggest that GSK-3 interacts with and phosphorylates delta-catenin and thereby negatively affects its stability by enabling its ubiquitination/proteosome-mediated proteolysis...
  23. pmc Xenopus delta-catenin is essential in early embryogenesis and is functionally linked to cadherins and small GTPases
    Dongmin Gu
    Department of Biochemistry and Molecular Biology, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    J Cell Sci 122:4049-61. 2009
    ..Collectively, our experiments indicate that delta-catenin has an essential role in amphibian development, and has functional links to cadherins and Rho-family GTPases...
  24. pmc Isoform- and dose-sensitive feedback interactions between paired box 6 gene and delta-catenin in cell differentiation and death
    Jiao Zhang
    Department of Hematology and Oncology, Southeast University School of Clinical Medicine, Nanjing, China
    Exp Cell Res 316:1070-81. 2010
    ..Therefore, delta-catenin expression is not only controlled by Pax6, but it also provides a feedback suppression mechanism for their functional interactions with important implications in cellular morphogenesis, apoptosis, and cancer...
  25. pmc Delta-catenin affects the localization and stability of p120-catenin by competitively interacting with E-cadherin
    Ilhwan Yang
    The College of Pharmacy and Research Institute for Drug Development, Chonnam National University, Gwangju, 500 757, Korea
    Mol Cells 29:233-7. 2010
    ..We show that successful binding by either one to E-cadherin adversely affects the stability of the other...
  26. pmc Rho kinase inhibitor Y-27632 facilitates recovery from experimental peripheral neuropathy induced by anti-cancer drug cisplatin
    Sarah E James
    Department of Anatomy and Cell Biology, Leo Jenkins Cancer Center, East Carolina University, Brody School of Medicine, 600 Moye Boulevard, Greenville, NC 27834, USA
    Neurotoxicology 31:188-94. 2010
    ..Sural nerve histology worsened in the absence of Y-27632 during recovery. These studies suggest that Rho kinase inhibitor Y-27632 can initiate regeneration of damaged nerves following cisplatin treatment...