Communication and Chemoprevention of Prostate Cancer

  • Mehta, Parmender P, (PI)

Project: Research project

Description

DESCRIPTION (provided by applicant): 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.
StatusFinished
Effective start/end date4/1/052/28/13

Funding

  • National Institutes of Health: $269,653.00
  • National Institutes of Health: $261,293.00
  • National Institutes of Health: $247,753.00
  • National Institutes of Health: $247,753.00
  • National Institutes of Health: $247,753.00

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Chemoprevention
Connexins
Gap Junctions
Androgens
Prostatic Neoplasms
Intercellular Junctions
Cholecalciferol
Vitamins
Cell Line
Prostate
Growth
Epithelial Cells
Hormones
Cell Adhesion Molecules
Nude Mice
Cell Adhesion
Cell Communication
alitretinoin
Neoplasms
Apoptosis

ASJC

  • Medicine(all)