Inappropriate Activation of the Androgen Receptor by Nonsteroids: Involvement of the Src Kinase Pathway and Its Therapeutic Implications

Desai, Sonal J.; Hong, Ai; Tepper, Clifford G.; Chen, Hong Wu; Kung, Hsing Jien

doi:10.1158/0008-5472.can-06-2582

Cited by 55 publications

(51 citation statements)

References 47 publications

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“…Finally, STAT3 phosphorylation might be influenced by the MAP kinase pathway in different ways. Studies performed with the herbal remedy magnolol in endothelial cells support the view that Jak-independent mechanisms also regulate STAT3 phosphorylation (Chen et al 2006). Magnolol suppressed IL-6 effect on STAT3 phosphorylation without causing an inhibition of Jak activation.…”

Section: Discussionmentioning

confidence: 81%

“…and androgen receptor in cancer www.endocrinology-journals.org number of genes to be similarly regulated by androgen and a compound that activates the PKA pathway. In case of AR activation by the neuropeptide bombesin, it was shown that the addition of bicalutamide to cells stimulated by bombesin causes a negative growth effect (Desai et al 2006). In addition, 72 genes, most of which are transcription factors and signal transduction proteins, were found to be similarly regulated by androgen and bombesin.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor

Malinowska¹,

Neuwirt²,

Cavarretta³

et al. 2009

Endocrine-Related Cancer

145

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It is hypothesized that ligand-independent activation of the androgen receptor is one of the mechanisms implicated in tumour progression. However, supportive evidence is limited to the effect of HER-2/neu that stimulates prostate cancer progression through activation of the androgen receptor. In the present study, we have asked whether the proinflammatory cytokine interleukin-6 (IL-6), which is known to stimulate androgen receptor activity and expression of its downstream target genes, may also induce growth of androgen-sensitive cells. We have found that IL-6 differentially regulates proliferation of LAPC-4 and MDA PCa 2b cells. In MDA PCa 2b cells, growth stimulation by IL-6 was reversed by administration of either the non-steroidal anti-androgen bicalutamide or the inhibitor of the mitogen-activated protein kinase pathway PD98059. Neither cell line was found to express endogenous IL-6. Interestingly, the treatment of those prostate cancer cells did not increase phosphorylation of STAT3. The effect of IL-6 on stimulation of androgen receptor activity in MDA PCa 2b cells was lower than that of androgen, comparable with findings reported by other researchers. However, growth of MDA PCa 2b xenografts in castrated animals treated with IL-6 was similar to that in non-castrated animals. In addition, bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo. Taken together, data in the present study demonstrate that IL-6 may cause growth of androgen receptorpositive tumours in vitro and in vivo through activation of the androgen receptor.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor

Malinowska¹,

Neuwirt²,

Cavarretta³

et al. 2009

Endocrine-Related Cancer

145

View full text Add to dashboard Cite

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“…Second, a decrease in the plasma membrane Na/K-ATPase ␣1 would impair the ability of cells to provide a counterregulation of Src and other growth-promoting pathways, especially in cellular structures such as tight junctions and adhesions where the Na/K-ATPase is highly concentrated in normal epithelial cells. This could occur when cellular Src is activated by steroid hormone/receptor interaction (40,41) or other factors such as increased activity of human epidermal growth factor receptor (42). Finally, increases in Src activity due to the down-regulation of ␣1 could potentiate VEGF production and then promote angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Na/K-ATPase Mimetic pNaKtide Peptide Inhibits the Growth of Human Cancer Cells

Zhang²,

Xie³

et al. 2011

Journal of Biological Chemistry

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Cells contain a large pool of nonpumping Na/K-ATPase that participates in signal transduction. Here, we show that the expression of ␣1 Na/K-ATPase is significantly reduced in human prostate carcinoma as well as in several human cancer cell lines. This down-regulation impairs the ability of Na/KATPase to regulate Src-related signaling processes. A supplement of pNaKtide, a peptide derived from ␣1 Na/K-ATPase, reduces the activities of Src and Src effectors. Consequently, these treatments stimulate apoptosis and inhibit growth in cultures of human cancer cells. Moreover, administration of pNaKtide inhibits angiogenesis and growth of tumor xenograft. Thus, the new findings demonstrate the in vivo effectiveness of pNaKtide and suggest that the defect in Na/K-ATPase-mediated signal transduction may be targeted for developing new anticancer therapeutics. Na/K-ATPase was originally discovered as an ion pump that is essential for cell vitality and provides a means for epithelium to secrete and/or absorb solutes and nutrients (1, 2). Recent studies have revealed that in addition to pumping ions across the cell membrane, Na/K-ATPase, specifically the ␣1 isoform, conducts many nonpumping functions, including scaffolding and signal transduction. As a signaling protein, it is involved in the formation of membrane structures such as tight junction and caveolae (3, 4). Moreover, a large fraction of cellular Na/KATPase is involved in tethering and regulating multiple protein and lipid kinases as well as membrane receptors (e.g. Src, human epidermal growth factor receptor, and PI3K) in a cellspecific manner (5, 6). Recently, the ␣1 Na/K-ATPase-Src receptor complex has been identified as one of the central components of ␣1 Na/K-ATPase-mediated signaling transduction (7). In this receptor complex, the Src SH2 domain binds to the second cytosolic domain, whereas the Src kinase domain interacts with the nucleotide binding (N) domain 4 of the ␣1 subunit. The latter interaction keeps Src in an inactive state (7). It is important to note that normal epithelial cells express approximately one million ␣1 Na/K-ATPase molecules (roughly five times the amount of Src). Thus, ␣1 Na/K-ATPase could provide at least two ways of regulating cellular Src activity. First, it could bind and keep Src in an inactive state. Consistently, when knock-out of one copy of the ␣1 gene caused a 20 -30% reduction in cellular ␣1 Na/K-ATPase, it produced a Ͼ2-fold increase in Src and ERK activities in tissues of ␣1 ϩ/Ϫ mice (8). Second, formation of the Na/K-ATPase-Src complex provides a functional receptor for endogenous cardiotonic steroids such as ouabain to regulate cellular signaling via Src and Src effectors (7, 9). Thus, changes in cellular ␣1 Na/K-ATPase would have a significant effect on cellular signaling events induced by either cardiotonic steroids or other growth factors through Src-related pathways.Based on the fact that the N domain of the ␣1 subunit binds and inhibits Src, we have recently made pNaKtide from the N domain of the human ␣1 subunit of...

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“…The methods for isolation of cell lysate, western blot analysis and immunoprecipitation have been described previously (Desai et al, 2006;Vinall et al, 2006).…”

Section: Western Blot Analysis and Immunoprecipitationmentioning

confidence: 99%

Inappropriate activation of androgen receptor by relaxin via β-catenin pathway

Liu¹,

Vinall²,

Tepper³

et al. 2007

Oncogene

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We have previously demonstrated that human H2-relaxin can mediate androgen-independent growth of LNCaP through a mechanism that involves the activation of the androgen receptor (AR) signaling pathway. The goal of the current study is to elucidate the mechanism(s) by which H2-relaxin causes activation of the AR pathway. Our data indicate that there is cross-talk between AR and components of the Wnt signaling pathway. Addition of H2-relaxin to LNCaP cells resulted in increased phosphorylation of protein kinase B (Akt) and inhibitory phosphorylation of glycogen synthase kinase-3b (GSK-3b) with subsequent cytoplasmic accumulation of b-catenin. Immunoprecipitation and immunocytochemical studies demonstrated that the stabilized b-catenin formed a complex with AR, which was then translocated into the nucleus. Chromatin immunoprecipitation analysis determined that the AR/b-catenin complex binds to the proximal region of the prostatespecific antigen promoter. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, using LY294002, prevented both H2-relaxin-mediated phosphorylation of Akt and GSK-3b and translocation of b-catenin/AR into the nucleus. Knockdown of b-catenin levels using a b-cateninspecific small interfering RNA inhibited H2-relaxin-induced AR activity. The combined data demonstrate that PI3K/ Akt and components of the Wnt pathway can facilitate H2-relaxin-mediated activation of the AR pathway.

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Inappropriate Activation of the Androgen Receptor by Nonsteroids: Involvement of the Src Kinase Pathway and Its Therapeutic Implications

Cited by 55 publications

References 47 publications

Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor

Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor

Na/K-ATPase Mimetic pNaKtide Peptide Inhibits the Growth of Human Cancer Cells

Inappropriate activation of androgen receptor by relaxin via β-catenin pathway

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