EGFR signaling pathway negatively regulates PSA expression and secretion via the PI3K-Akt pathway in LNCaP prostate cancer cells

Hakariya, Tomoaki; Shida, Yohei; Sakai, Hideki; Kanetake, Hiroshi; Igawa, Tsukasa

doi:10.1016/j.bbrc.2006.01.106

Cited by 19 publications

(20 citation statements)

References 27 publications

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“…However, other studies in LNCaP cells found that EGF or HB-EGF decrease AR expression, consistent with the findings in the current study (28–31). One factor that may contribute to differences between studies is that results in some cases are based on transfected AR (15, 18).…”

Section: Discussionsupporting

confidence: 93%

“…In other studies, heparin binding EGF (HB-EGF) was found to decrease AR protein expression through activation of mTOR and decreased AR mRNA translation (29, 30). EGF also decreased PSA expression and secretion via the PI3K/Akt pathway in androgen-independent LNCaP-C81 cells (31). Finally, Akt in LNCaP cells may phosphorylate AR and enhance its ubiquitination by Mdm2 and degradation, but this seems to be dependent on cell passage number (32–36).…”

Section: Introductionmentioning

confidence: 99%

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Androgen Receptor Expression in Prostate Cancer Cells Is Suppressed by Activation of Epidermal Growth Factor Receptor and ErbB2

et al. 2009

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Prostate cancers (PCa) that relapse after androgen deprivation therapies [castration-resistant PCa (CRPC)] express high levels of androgen receptor (AR) and androgen-regulated genes, and evidence from several groups indicates that ErbB family receptor tyrosine kinases [epidermal growth factor (EGF) receptor (EGFR) and ErbB2] may contribute to enhancing this AR activity. We found that activation of these kinases with EGF and heregulin-β1 rapidly (within 8 hours) decreased expression of endogenous AR and androgen-regulated PSA in LNCaP PCa cells. AR expression was similarly decreased in LAPC4 and C4-2 cells, but not in the CWR22Rv1 PCa cell line. The rapid decrease in AR was not due to increased AR protein degradation and was not blocked by phosphatidylinositol 3-kinase (LY294002) or MEK (UO126) inhibitors. Significantly, AR mRNA levels in LNCaP cells were markedly decreased by EGF and heregulin-β1, and experiments with actinomycin D to block new mRNA synthesis showed that AR mRNA degradation was increased. AR mRNA levels were still markedly decreased by EGF and heregulin-β1 in LNCaP cells adapted to growth in androgen-depleted medium, although AR protein levels did not decline due to increased AR protein stability. These findings show that EGFR and ErbB2 can negatively regulate AR mRNA and may provide an approach to suppress AR expression in CRPC.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Androgen Receptor Expression in Prostate Cancer Cells Is Suppressed by Activation of Epidermal Growth Factor Receptor and ErbB2

et al. 2009

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“…Moreover, when cells were seeded in medium devoid of EGF but at a density which allows intercellular junctions and cell polarisation, they were able to re-enter the cell cycle after an EGF stimulation, thus leading to a sustained ERK phosphorylation stimulation of MAPK and a loss in AR expression. The EGF-mediated AR down-regulation in VDEC is linked to a reduction of AR mRNA accumulation suggesting a regulation at transcriptional or post-transcriptional level that is consistent with reported studies on tumoural cell sublines (Mizokami et al 1992, Hakariya et al 2006. Contrarily to what was observed in LNCaP cells by Hakarya et al, EGF-induced AR signalling repression is abolished in the presence of a MAPK inhibitor such as PD98059 in VDEC, suggesting the existence of cell type differences in the crosstalk between intracellular signalling pathways, which could be altered in tumoural cells.…”

Section: Discussionsupporting

confidence: 89%

Crosstalk between androgen receptor and epidermal growth factor receptor-signalling pathways: a molecular switch for epithelial cell differentiation

Léotoing¹,

Manin²,

Monté³

et al. 2007

Journal of Molecular Endocrinology

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In the male, androgens promote growth and differentiation of sex reproductive organs through ligand activation of the androgen receptor (AR). Here, we show that androgens are not major actors of the cell cycle arrest associated with the differentiation process, and that the epidermal growth factor (EGF)-mediated signalling interferes with AR activities to regulate androgen response when epithelial cells are differentiated. Higher AR expression and enhanced androgen responsiveness correlate with reduction of phosphorylated ERK1/2 over differentiation. These modifications are associated with recruitment of cells in phase G 0 /G 1 , up-regulation of p27 kip1 , down-regulation of p21Cip1 and p53 proteins, and accumulation of hypo-phosphorylated Rb. Exposure to EGF reduces AR expression levels and blocks androgendependent transcription in differentiated cells. It also restores p53 and p21Cip1 levels, Rb hyper-phosphorylation, ERK1/2 activation and promotes cell cycle re-entry as p27 kip1 protein levels are decreased. Treatment with a MEK inhibitor reverses the EGF-mediated AR down-regulation in differentiated cells, thus suggesting the existence of an inverse correlation between EGF and androgen signalling in non-tumoural epithelia. Interestingly, when androgen signalling is set in differentiated cells, dihydrotestosterone exerts an inhibitory effect on ERK activity but paradoxically does not modify EGFR (ErbB1) phosphorylation, indicating that androgens are able to disrupt the EGFR-ERK cascade. Overall, our data demonstrate the existence of a balance between AR and mitogen-activated protein kinase activities that favours either the maintenance of differentiated conditions or the enhancement of cell proliferation capacities.

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“…There are also 41 common targets of the down-regulated miRNAs in all treatment conditions (Figure 7B). Some of the targets are known oncoproteins, which includes EGFR [99], VEGFA [100], ZBTB7 (POKEMON) [101], acid phosphatase 2(ACP2) [102] and NFKB1 [103]. Additionally, proteins that are overexpressed in cancer cells are among the targets of down-regulated miRNAs in different treatment conditions, which includes Wnt3A [104], PPARα [105], UCP2 [106], CSF1 [107], and MED1 [108].…”

Section: Resultsmentioning

confidence: 99%

MicroRNA expressions associated with progression of prostate cancer cells to antiandrogen therapy resistance

et al. 2014

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BackgroundDevelopment of resistance to androgen deprivation therapy (ADT) is a major obstacle for the management of advanced prostate cancer. Therapies with androgen receptor (AR) antagonists and androgen withdrawal initially regress tumors but development of compensatory mechanisms including AR bypass signaling leads to re-growth of tumors. MicroRNAs (miRNAs) are small regulatory RNAs that are involved in maintenance of cell homeostasis but are often altered in tumor cells.ResultsIn this study, we determined the association of genome wide miRNA expression (1113 unique miRNAs) with development of resistance to ADT. We used androgen sensitive prostate cancer cells that progressed to ADT and AR antagonist Casodex (CDX) resistance upon androgen withdrawal and treatment with CDX. Validation of expression of a subset of 100 miRNAs led to identification of 43 miRNAs that are significantly altered during progression of cells to treatment resistance. We also show a correlation of altered expression of 10 proteins targeted by some of these miRNAs in these cells.ConclusionsWe conclude that dynamic alterations in miRNA expression occur early on during androgen deprivation therapy, and androgen receptor blockade. The cumulative effect of these altered miRNA expression profiles is the temporal modulation of multiple signaling pathways promoting survival and acquisition of resistance. These early events are driving the transition to castration resistance and cannot be studied in already developed CRPC cell lines or tissues. Furthermore our results can be used a prognostic marker of cancers with a potential to be resistant to ADT.

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EGFR signaling pathway negatively regulates PSA expression and secretion via the PI3K-Akt pathway in LNCaP prostate cancer cells

Cited by 19 publications

References 27 publications

Androgen Receptor Expression in Prostate Cancer Cells Is Suppressed by Activation of Epidermal Growth Factor Receptor and ErbB2

Androgen Receptor Expression in Prostate Cancer Cells Is Suppressed by Activation of Epidermal Growth Factor Receptor and ErbB2

Crosstalk between androgen receptor and epidermal growth factor receptor-signalling pathways: a molecular switch for epithelial cell differentiation

MicroRNA expressions associated with progression of prostate cancer cells to antiandrogen therapy resistance

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