Journal
PROSTATE
Volume 74, Issue 11, Pages 1118-1131Publisher
WILEY
DOI: 10.1002/pros.22828
Keywords
androgen receptor; human prostate epithelial cells; c-MYC; -catenin; TCF-4
Categories
Funding
- NIH [R01DK52645, U54CA091409]
- NIH-Prostate SPORE [P50 CA058236]
- Maryland Stem Cell Research Fund [MSCRFII-0428-00]
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INTRODUCTION Physiologic testosterone continuously stimulates prostate stromal cell secretion of paracrine growth factors (PGFs), which if unopposed would induce hyperplastic overgrowth of normal prostate epithelial cells (PrECs). METHODS Lentiviral shRNA stable knock down of c-MYC, -catenin, or TCF-4 completely inhibits normal (i.e., non-transformed) human PrECs growth. c-MYC enhancer driven reporter expression and growth is inhibited by two chemically distinct molecules, which prevent -catenin signaling either by blocking TCF-4 binding (i.e., toxoflavin) or by stimulating degradation (i.e., AVX939). Recombinant DKK1 protein at a dose, which inhibits activation of canonical Wnt signaling does not inhibit PrEC growth. Nuclear -catenin translocation and PrEC growth is prevented by both lack of PGFs or Akt inhibitor-I. Growth inhibition induced by lack of PGFs, toxoflavin, or Akt inhibitor-I is overcome by constitutive c-MYC transcription. RESULTS In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen binding to AR suppressing c-MYC transcription, resulting in G0 arrest/terminal differentiation independent of Rb, p21, p27, FoxP3, or down regulation of growth factors receptors and instead involves androgen-induced formation of AR/-catenin/TCF-4 complexes, which suppress c-MYC transcription. Such suppression does not occur when AR is mutated in its zinc-finger binding domain. DISCUSSION Proliferation of non-transformed human PrECs is dependent upon c-MYC transcription via formation/binding of -catenin/TCF-4 complexes at both 5 and 3 c-MYC enhancers stimulated by Wnt-independent, PGF induced Akt signaling. In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen-induced formation of AR/-catenin/TCF-4 complexes, which retains binding to 3 c-MYC enhancer, but now suppresses c-MYC transcription. Prostate 74:1118-1131, 2014. (c) 2014 Wiley Periodicals, Inc.
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