IL-4 and androgen receptor signaling in prostate cancer

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Almost all patients with advanced prostate cancer respond initially to androgen deprivation and antiandrogen therapy. However, in virtually all patients, prostate cancer will recur due to growth of cancer cells that do not require androgens. While the exact mechanisms are not known, accumulating evidence indicates that abnormal (i.e., ligand-independent) activation of androgen receptor (AR) and development of apoptotic resistant cells contribute to prostate cancer androgen-independent growth. Our data demonstrates that interleukin-4 (IL-4) activates AR signaling in the presence of very low levels of androgen or in the absence of androgen. In addition, we have found that IL-4 protects androgen sensitive LNCaP human prostate cancer cells from apoptotic cell death initiated by androgen deprivation. IL-4 activates Akt, NF-kappaB and Stat6 in prostate cancer cells. NF-kappaB activation by IL-4 appears to occur by the Akt pathway. The activity of NF-kappaB and Stat6 is elevated in prostate cancer compared to normal prostate. These findings are important because the Akt->NF-kappaB signaling pathway has been demonstrated to promote tumorigenesis by inhibiting apoptosis. The hypothesis is that IL-4 induced cell signaling is a critical regulator of AR signaling and facilitates androgen-independent growth of prostate cancer. To test this hypothesis, 3 aims are proposed. 1. To determine the role of IL-4 on AR activation and androgen responsiveness of prostate cancer cells. Prostate cancer cell lines that express increased levels of IL-4 will be established. The effects of constitutive expression of IL-4 on androgen-mediated prostate cancer cell growth in vitro and in vivo and on the expression of androgen-inducible genes will be examined. 2. To determine the role of Akt->NF-kappaB and Stat6 signaling in IL-4 mediated AR activation and androgen responsiveness. Inhibitors and dominant negative mutants or forced expression of activated Stat6 and Akt->NF-kappaB will be used to determine the requirement of these signaling pathways in IL-4 mediated AR activation. 3. To determine whether Akt-> NF-kappaB signaling is required for IL-4 mediated survival of prostate cancer cells.
StatusFinished
Effective start/end date4/1/052/29/12

Funding

  • National Institutes of Health: $222,210.00
  • National Institutes of Health: $213,141.00
  • National Institutes of Health: $226,463.00
  • National Institutes of Health: $213,141.00
  • National Institutes of Health: $229,542.00

ASJC

  • Medicine(all)

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