Constitutive activation of PI3K-Akt and NF-κB during prostate cancer progression in autochthonous transgenic mouse model

Shukla, Sanjeev; MacLennan, Gregory T.; Marengo, Susan Ruth; Resnick, Martin I.; Gupta, Sanjay

doi:10.1002/pros.20217

Cited by 111 publications

(119 citation statements)

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“…We observed that as cancer progressed from undetectable cancer at 8 weeks to poorly differentiated adenocarcinoma at 32 weeks, there was a considerable upregulation in the phosphorylation of NFκB at Ser 536 . These results are consistent with previous observation where NFκB was observed to be upregulated, with increasing age in TRAMP mice (22) and prostate carcinoma cells (23,24). This up-regulation of this transcription factor was significantly inhibited (P<0.001) in the groups given GTP in drinking water (Fig.…”

Section: And Identified That Igf-i/ Igfbp-3 Signaling Pathway Is a Prsupporting

confidence: 93%

Suppression of NFκB and its Regulated Gene Products by Oral Administration of Green Tea Polyphenols in an Autochthonous Mouse Prostate Cancer Model

et al. 2008

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Purpose-This study examines the role of cell survival/apoptosis related proteins involved in NFκB signaling pathways and its associated events in GTP-induced chemoprevention of prostate cancer in TRAMP mice.Methods-Mice were given 0.1% GTP as drinking fluid. Western blot and immunohistochemical analysis performed to examine NFκB and its regulated pathway in response to GTP.Results-Our data demonstrated increased expression of NFκB, IKKα, IKKβ, RANK, NIK and STAT-3 in dorso-lateral prostate of TRAMP mice as a function of age and tumor growth and continuous GTP infusion for 32 weeks resulted in substantial reduction in these proteins. The levels of transcription factor osteopontin, a non-collagenous extracellular matrix protein, were also downregulated. Inhibition of NFκB signaling is known to activate apoptotic and inhibit antiapoptotic proteins. Therefore, we analyzed Bax and Bcl 2 levels in the dorsolateral prostate of TRAMP mice fed GTP and observed a shift in balance between Bax and Bcl 2 favoring apoptosis.Conclusions-Based on the data we suggest that oral consumption of GTP might inhibit osteopontin and NFκB signaling that may contribute to induction of apoptosis observed in GTP fed TRAMP mice.

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Section: And Identified That Igf-i/ Igfbp-3 Signaling Pathway Is a Prsupporting

confidence: 93%

Suppression of NFκB and its Regulated Gene Products by Oral Administration of Green Tea Polyphenols in an Autochthonous Mouse Prostate Cancer Model

et al. 2008

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“…distribution of chronic inflammation in radical prostatectomy specimens with up-regulation of survival factor, Bcl-2 [24]. Simultaneously, NF-kB/p65 has been shown to be constitutively activated in both human prostate adenocarcinoma and in the autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and is associated with tumor progression due to transcriptional regulation of NF-kBresponsive genes [13,25]. It is still unclear whether increases in pro-inflammatory cytokine production are the cause or the consequence of NF-kB activation in the prostate during tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Molecular imaging of NF‐kappaB in prostate tissue after systemic administration of IL‐1β

et al. 2007

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BACKGROUND. Activation of nuclear-factor kappaB (NF-kB) influences the transcription of number of genes, many of which participate in inflammatory responses and tumor development. A wide range of human cancers and inflammatory disorders express inappropriate regulation of NF-kB. The role of NF-kB in intraprostatic inflammation has not been elucidated. METHODS. Using transgenic NF-kB-Luciferase Tag mice coupled to the luciferase reporter gene, we performed serial, noninvasive in vivo and ex vivo molecular imaging of NF-kB activation in the mouse body after systemic administration of mouse pro-inflammatory cytokines: TNF-a, IL-6, and IL-1b at 10 mg/kg body weights. In some experiments, pretreatment with dexamethasone (10 mg/kg) was used to modulate the cytokine-induced NF-kB-dependent luminescence in vivo. RESULTS. Treatment of NF-kB-Luc mice with cytokines increased luminescence in a time-and organ-specific manner. Highest levels of NF-kB-dependent luminescence were observed approximately 3-4 hr after IL-1b administration. An important finding was the cumulative effect of IL-1b to activate NF-kB in the prostate during chronic administration. CONCLUSIONS. The molecular imaging of NF-kB activity might be an attractive approach to distinguish the role of cytokine-induced NF-kB signaling in intraprostatic inflammation and prostate cancer development. Since dexamethasone, a known NF-kB inhibitor, could reduce the IL-1b-induced NF-kB-dependent luminescence in the prostate, NF-kB-Luc mice might be useful tool to screen potential candidate drugs for treatment of inflammation and tumor associated with aberrant NF-kB activity.

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“…Constitutive NFjB activation and subsequent Bcl-2 increase mark hormone refractory PrCa. 42,56,57 Conversely, AR and NFjB counteract in transcription assays. 58 Indeed, reporter assays showed high basal NFjB activity in PC-3 cells, which was decreased upon transient transfection with AR WT and diminished further by DHT (Fig.…”

Section: Ar Activation Lowered Nfjb Levels and Activitymentioning

confidence: 99%

“…40 Noteworthy, in PrCa AR status inversely correlates with NFjB activity. 25,41,42 We analyzed how inducible AR affects the tumorigenicity of AR-null PC-3 cells. Unexpectedly, the AR(1) PC-3 cells became less tumorigenic on ambient testosterone background.…”

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confidence: 99%

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

Nelius

Filleur

Yemelyanov

et al. 2007

Intl Journal of Cancer

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The androgen role in the maintenance of prostate epithelium is subject to conflicting opinions. While androgen ablation drives the regression of normal and cancerous prostate, testosterone may cause both proliferation and apoptosis. Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor (AR), however no mechanistic explanation was offered. In this paper we demonstrate in vivo anti-tumor effect of the AR on prostate cancer growth and identify its molecular mediators. We analyzed the effect of AR on the tumorigenicity of prostate cancer cells. Unexpectedly, the AR-expressing cells formed tumors in male mice at a much lower rate than the AR-negative controls. Moreover, the AR-expressing tumors showed decreased vascularity and massive apoptosis. AR expression lowered the angiogenic potential of cancer cells, by increasing secretion of an anti-angiogenic protein, thrombospondin-1. AR activation caused a decrease in RelA, a subunit of the pro-survival transcription factor NFjB, reduced its nuclear localization and transcriptional activity. This, in turn, diminished the expression of its anti-apoptotic targets, Bcl-2 and IL-6. Increased apoptosis within AR-expressing tumors was likely due to the NFjB suppression, since it was restricted to the cells lacking nuclear (active) NFjB. Thus we for the first time identified combined decrease of NFjB and increased TSP1 as molecular events underlying the AR anti-tumor activity in vivo. Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal, a standard treatment for early-stage prostate cancer. ' 2007 Wiley-Liss, Inc.

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Constitutive activation of PI3K-Akt and NF-κB during prostate cancer progression in autochthonous transgenic mouse model

Abstract: Differential expression pattern of P I3 K-Akt, NF-kappaB and I kappaB during prostate cancer progression in TRAMP mice suggest that these molecules represent potential molecular targets for prevention and/or therapeutic intervention.

Cited by 111 publications

References 53 publications

Suppression of NFκB and its Regulated Gene Products by Oral Administration of Green Tea Polyphenols in an Autochthonous Mouse Prostate Cancer Model

Suppression of NFκB and its Regulated Gene Products by Oral Administration of Green Tea Polyphenols in an Autochthonous Mouse Prostate Cancer Model

Molecular imaging of NF‐kappaB in prostate tissue after systemic administration of IL‐1β

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

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