Communication and Chemoprevention of Prostate Cancer

Summary

Principal Investigator: Parmender P Mehta
Abstract: The role of cell contact-dependent communication in the progression of prostate cancer from a slow-growing hormone (androgen)-dependent state to a highly malignant, hormone-independent state is not fully understood. Cell contact-dependent communication is often mediated by cell adhesion molecules which often get clustered into macromolecular assemblies called cell junctions. Gap junctions, which are formed of proteins called connexins, are a special class of cell junctions that provide a direct cell-cell communication pathway for the passage of signaling molecules between adjoining cells. Our studies have shown that epithelial cells from prostate tumors show diminished, or loss of, connexin expression during prostate cancer progression. Re-expression of connexins in connexin-deficient, androgen-dependent prostate cancer cell line, LNCaP, restores communication and retards growth, whereas that into invasive, androgen-independent cell line, PC-3, results in intracellular connexin accumulation due to impaired trafficking. Intriguingly, treatment of connexin-expressing LNCaP cells with the androgens, which are known to maintain the differentiated state of normal prostate epithelial cells, and facilitate prostate cancer progression, as well as with chemopreventive agents - such as all-trans- and 9-Cis-retinoic acids and 1,25 (OH)2 vitamin D3 either alone or in combination - facilitates the assembly of connexins into gap junctions and their removal degrades gap junctions. We have hypothesized that trafficking of connexins and their assembly into gap junctions are regulated by cellcell adhesion, which becomes defective during the progression of prostate cancer .We have further hypothesized that the physiological modulators of prostate growth and cancer - such as the androgens, alltrans- and 9-Cis-retinoic acids and 1,25 (OH)2 D3 - act as chemopreventive agents by regulating the trafficking of connexins and their assembly and disassembly into gap junctions either directly or indirectly through their effect on cell-cell adhesion. We have proposed 4 specific aims to test these hypotheses. Aim 1 will elucidate the cellular and molecular mechanisms by which androgens and 9-Cis-retinoic acid and 1,25 (OH)2 D3, either alone or in combination, enhance the formation of gap junctions. In aim 2 we will analyze how these agents prevent the degradation of gap junctions in androgen-independent and dependent prostate cancer cell lines. Aim 3 investigates whether androgens and 9-Cis-retinoic acids and 1,25 (OH)2 vitamin D3, enhance the formation of gap junctions between androgen-dependent and androgen-independent prostate cancer cells. Aim 4 will test formation and degradation of gap junctions are regulated by androgens, 9-Cis-retinoic acid and 1,25 (OH)2 vitamin Da in tumors at Ectopic and orthotopic sites in nude mice. Because of the potential interactions among androgens, 9-Cis-retinoic acid and 1,25 (OH)2 vitamin Da receptor pathways, an investigation into their additive and/or synergistic effects on the assembly and disassembly of connexins into gap junctions may shed light on the mechanism by which these agents affect growth, differentiation and apoptosis of normal and prostate cancer cells in vitro and in vivo and act as chemopreventive agents.
Funding Period: 2005-04-01 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Assembly of connexin43 into gap junctions is regulated differentially by E-cadherin and N-cadherin in rat liver epithelial cells
    Rajgopal Govindarajan
    Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Mol Biol Cell 21:4089-107. 2010
  2. pmc Phosphorylation on Ser-279 and Ser-282 of connexin43 regulates endocytosis and gap junction assembly in pancreatic cancer cells
    Kristen E Johnson
    Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Mol Biol Cell 24:715-33. 2013
  3. pmc E-cadherin differentially regulates the assembly of Connexin43 and Connexin32 into gap junctions in human squamous carcinoma cells
    Souvik Chakraborty
    Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
    J Biol Chem 285:10761-76. 2010
  4. pmc Androgen-regulated formation and degradation of gap junctions in androgen-responsive human prostate cancer cells
    Shalini Mitra
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Mol Biol Cell 17:5400-16. 2006
  5. ncbi Introduction: a tribute to cell-to-cell channels
    Parmender P Mehta
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
    J Membr Biol 217:5-12. 2007
  6. pmc Functions of normal and malignant prostatic stem/progenitor cells in tissue regeneration and cancer progression and novel targeting therapies
    Murielle Mimeault
    and Surinder K Batra, Ph D, Department of Biochemistry and Molecular Biology, Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198 5870, USA
    Endocr Rev 29:234-52. 2008
  7. pmc MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells
    Pallavi Chaturvedi
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198 5870, USA
    Cancer Res 68:2065-70. 2008

Scientific Experts

  • M Mimeault
  • Parmender P Mehta
  • Souvik Chakraborty
  • Shalini Mitra
  • Kristen E Johnson
  • Keith R Johnson
  • Margaret J Wheelock
  • Rajgopal Govindarajan
  • Matthias M Falk
  • Pallavi Chaturvedi
  • Surinder K Batra
  • Parul Katoch
  • Linda S Kelsey
  • Steve H Caplan
  • Michael A Hollingsworth
  • Ajay P Singh
  • Pankaj K Singh
  • Jane L Meza
  • Sangeeta Bafna
  • Subhankar Chakraborty
  • Subhash C Chauhan
  • Xiao hong Song
  • Kristen Johnson
  • Lakshmanan Annamalai

Detail Information

Publications7

  1. pmc Assembly of connexin43 into gap junctions is regulated differentially by E-cadherin and N-cadherin in rat liver epithelial cells
    Rajgopal Govindarajan
    Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Mol Biol Cell 21:4089-107. 2010
    ....
  2. pmc Phosphorylation on Ser-279 and Ser-282 of connexin43 regulates endocytosis and gap junction assembly in pancreatic cancer cells
    Kristen E Johnson
    Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Mol Biol Cell 24:715-33. 2013
    ..Thus the differential phosphorylation of Cx43 on Ser-279 and Ser-282 is fine-tuned to control Cx43's endocytosis and assembly into gap junctions...
  3. pmc E-cadherin differentially regulates the assembly of Connexin43 and Connexin32 into gap junctions in human squamous carcinoma cells
    Souvik Chakraborty
    Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
    J Biol Chem 285:10761-76. 2010
    ....
  4. pmc Androgen-regulated formation and degradation of gap junctions in androgen-responsive human prostate cancer cells
    Shalini Mitra
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Mol Biol Cell 17:5400-16. 2006
    ....
  5. ncbi Introduction: a tribute to cell-to-cell channels
    Parmender P Mehta
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
    J Membr Biol 217:5-12. 2007
  6. pmc Functions of normal and malignant prostatic stem/progenitor cells in tissue regeneration and cancer progression and novel targeting therapies
    Murielle Mimeault
    and Surinder K Batra, Ph D, Department of Biochemistry and Molecular Biology, Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198 5870, USA
    Endocr Rev 29:234-52. 2008
    ....
  7. pmc MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells
    Pallavi Chaturvedi
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198 5870, USA
    Cancer Res 68:2065-70. 2008
    ..Our findings add a new dimension to MUC4 function as a modulator of cell signaling and provide mechanistic evidence for its role in pancreatic cancer progression...