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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA109441-01A1
Application #
6928134
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$229,542
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Tummala, Ramakumar; Lou, Wei; Gao, Allen C et al. (2017) Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells. Mol Cancer Ther 16:2770-2779
Zhu, Yezi; Liu, Chengfei; Tummala, Ramakumar et al. (2013) RhoGDI? downregulates androgen receptor signaling in prostate cancer cells. Prostate 73:1614-22
Nadiminty, Nagalakshmi; Tummala, Ramakumar; Liu, Chengfei et al. (2013) NF-?B2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther 12:1629-37
Liu, Chengfei; Zhu, Yezi; Lou, Wei et al. (2013) Functional p53 determines docetaxel sensitivity in prostate cancer cells. Prostate 73:418-27
Nadiminty, Nagalakshmi; Tummala, Ramakumar; Lou, Wei et al. (2012) MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of Myc expression in prostate cancer cells. J Biol Chem 287:1527-37
Nadiminty, Nagalakshmi; Tummala, Ramakumar; Lou, Wei et al. (2012) MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth. PLoS One 7:e32832
Sun, Meng; Liu, Chengfei; Nadiminty, Nagalakshmi et al. (2012) Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion. Prostate 72:82-9
Zhu, Yezi; Tummala, Ramakumar; Liu, Chengfei et al. (2012) RhoGDI? suppresses growth and survival of prostate cancer cells. Prostate 72:392-8
Nadiminty, Nagalakshmi; Gao, Allen C (2012) Mechanisms of persistent activation of the androgen receptor in CRPC: recent advances and future perspectives. World J Urol 30:287-95
Liu, Chengfei; Nadiminty, Nagalakshmi; Tummala, Ramakumar et al. (2011) Andrographolide targets androgen receptor pathway in castration-resistant prostate cancer. Genes Cancer 2:151-9

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