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TNFα-mediated loss of β-catenin/E-cadherin association and subsequent increase in cell migration is partially restored by NKX3.1 expression in prostate cells.

Debelec-Butuner B, Alapinar C, Ertunc N, Gonen-Korkmaz C, Yörükoğlu K, Korkmaz KS - PLoS ONE (2014)

Bottom Line: Nevertheless, ectopic expression of NKX3.1, which is degraded upon proinflammatory cytokine exposure in inflammation, was found to induce the degradation of β-catenin by inhibiting Akt(S473) phosphorylation, therefore, partially rescued the disrupted β-catenin-E-cadherin interaction as well as the cell migration in LNCaP cells upon cytokine exposure.As, the disrupted localization of β-catenin at the cell membrane as well as increased Akt(S308) priming phosphorylation was observed in human prostate tissues with prostatic inflammatory atrophy (PIA), high-grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma lesions correlated with loss of NKX3.1 expression.Thus, the data indicate that the β-catenin signaling; consequently sub-cellular localization is deregulated in inflammation, associates with prostatic atrophy and PIN pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, Cancer Biology Laboratory, Faculty of Engineering, Ege University, Bornova, Izmir, Turkey; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey.

ABSTRACT
Inflammation-induced carcinogenesis is associated with increased proliferation and migration/invasion of various types of tumor cells. In this study, altered β-catenin signaling upon TNFα exposure, and relation to loss of function of the tumor suppressor NKX3.1 was examined in prostate cancer cells. We used an in vitro prostate inflammation model to demonstrate altered sub-cellular localization of β-catenin following increased phosphorylation of Akt(S473) and GSK3β(S9). Consistently, we observed that subsequent increase in β-catenin transactivation enhanced c-myc, cyclin D1 and MMP2 expressions. Consequently, it was also observed that the β-catenin-E-cadherin association at the plasma membrane was disrupted during acute cytokine exposure. Additionally, it was demonstrated that disrupting cell-cell interactions led to increased migration of LNCaP cells in real-time migration assay. Nevertheless, ectopic expression of NKX3.1, which is degraded upon proinflammatory cytokine exposure in inflammation, was found to induce the degradation of β-catenin by inhibiting Akt(S473) phosphorylation, therefore, partially rescued the disrupted β-catenin-E-cadherin interaction as well as the cell migration in LNCaP cells upon cytokine exposure. As, the disrupted localization of β-catenin at the cell membrane as well as increased Akt(S308) priming phosphorylation was observed in human prostate tissues with prostatic inflammatory atrophy (PIA), high-grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma lesions correlated with loss of NKX3.1 expression. Thus, the data indicate that the β-catenin signaling; consequently sub-cellular localization is deregulated in inflammation, associates with prostatic atrophy and PIN pathology.

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The CM exposure influences prostate cell progression through increasing cytoplasmic accumulation of β-catenin, which subsequently leads increased migration.Further, inflammation-mediated Akt activity and subsequent β-catenin transactivation can be deregulated by androgen responsive factor NKX3.1, stabilizing the p-β-catenin(S33) pool, eventually influencing the maintenance of the intact β-catenin/E-cadherin association at the plasma membrane.
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pone-0109868-g007: The CM exposure influences prostate cell progression through increasing cytoplasmic accumulation of β-catenin, which subsequently leads increased migration.Further, inflammation-mediated Akt activity and subsequent β-catenin transactivation can be deregulated by androgen responsive factor NKX3.1, stabilizing the p-β-catenin(S33) pool, eventually influencing the maintenance of the intact β-catenin/E-cadherin association at the plasma membrane.

Mentions: The deregulation of β-catenin function may promote tumorigenesis by altering gene transcription, increasing cell migration and abrogating cell polarity [11]. Thus, β-catenin contributes to prostate carcinogenesis at least in two ways. First, enhanced nuclear translocation of β-catenin results in increased proliferation, as seen in other cancer types. Second, tissue-specific molecular changes may dominate during tumorigenesis. Likewise, activation of the androgen receptor (AR) transactivation function is promoted by nuclear localization of β-catenin in prostate cells. Therefore, tissue-specific transcription factors (TCFs) and AR crosstalk with β-catenin may contribute to the progression of prostate hyperplasia, cell differentiation and tumorigenesis in prostate [2], [32]. Additionally, β-catenin stabilization and nuclear localization result in the upregulation of the β-catenin target genes cyclin D1 and c-myc, which can lead to the formation of the prostatic intraepithelial neoplasia (PIN)-like phenotype [33]. Further, activated Akt stabilizes β-catenin via inhibition of GSK3β [34] and directly phosphorylates β-catenin at S552, thereby promotes β-catenin transactivation [9]. Based on previous reports [35] and our findings reported here, we suggest that mimicking TNFα-mediated inflammation [20] in prostate cells results in a significant increase in pAkt(S473), which consequently inhibits GSK3β kinase activity by increasing the phosphorylation from (S9) residue (Figure 1E). Furthermore, the decrease in β-catenin(S33) phosphorylation implies that either proteosomal degradation is activated and β-catenin(S33) is depleted by ubiquitination dependent proteosomal machinery, or there can be an increase in the stabilizing phosphorylation of β-catenin(S552), which suppresses the S33 phosphorylation (Figure 1E) by enhanced Akt activity. As the majority of the total β-catenin localizes at the cell membrane, and associates with E-cadherin at adherent junctions, whereas the total β-catenin level does not change, we suggest that CM-mediated Akt activation abrogates the E-cadherin and β-catenin association at plasma membrane localization. This hypothesis is confirmed by the increasing ratios of nuclear/cytoplasmic and cytoplasmic/membrane localization of β-catenin in our studies and the schema was drawn accordingly (Figure 7). Moreover, in a previous study, Lamb et. al. [36] have demonstrated that blocking E-cadherin leads to a decrease in AKT activation. This data suggests that cell-cell adhesion is mediated by E-cadherin interaction that promotes the secretory-like cell survival through PI3K signaling. Hence, the putative mechanism can be a crosstalk between Akt signaling and E-cadherin localization, and its expression does not change in CM, but with ectopic NKX3.1 expression, E-cadherin localization to cell membrane might be facilitated through EGFR pathway. Ascertain the putative mechanism requires further studies.


TNFα-mediated loss of β-catenin/E-cadherin association and subsequent increase in cell migration is partially restored by NKX3.1 expression in prostate cells.

Debelec-Butuner B, Alapinar C, Ertunc N, Gonen-Korkmaz C, Yörükoğlu K, Korkmaz KS - PLoS ONE (2014)

The CM exposure influences prostate cell progression through increasing cytoplasmic accumulation of β-catenin, which subsequently leads increased migration.Further, inflammation-mediated Akt activity and subsequent β-catenin transactivation can be deregulated by androgen responsive factor NKX3.1, stabilizing the p-β-catenin(S33) pool, eventually influencing the maintenance of the intact β-catenin/E-cadherin association at the plasma membrane.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215977&req=5

pone-0109868-g007: The CM exposure influences prostate cell progression through increasing cytoplasmic accumulation of β-catenin, which subsequently leads increased migration.Further, inflammation-mediated Akt activity and subsequent β-catenin transactivation can be deregulated by androgen responsive factor NKX3.1, stabilizing the p-β-catenin(S33) pool, eventually influencing the maintenance of the intact β-catenin/E-cadherin association at the plasma membrane.
Mentions: The deregulation of β-catenin function may promote tumorigenesis by altering gene transcription, increasing cell migration and abrogating cell polarity [11]. Thus, β-catenin contributes to prostate carcinogenesis at least in two ways. First, enhanced nuclear translocation of β-catenin results in increased proliferation, as seen in other cancer types. Second, tissue-specific molecular changes may dominate during tumorigenesis. Likewise, activation of the androgen receptor (AR) transactivation function is promoted by nuclear localization of β-catenin in prostate cells. Therefore, tissue-specific transcription factors (TCFs) and AR crosstalk with β-catenin may contribute to the progression of prostate hyperplasia, cell differentiation and tumorigenesis in prostate [2], [32]. Additionally, β-catenin stabilization and nuclear localization result in the upregulation of the β-catenin target genes cyclin D1 and c-myc, which can lead to the formation of the prostatic intraepithelial neoplasia (PIN)-like phenotype [33]. Further, activated Akt stabilizes β-catenin via inhibition of GSK3β [34] and directly phosphorylates β-catenin at S552, thereby promotes β-catenin transactivation [9]. Based on previous reports [35] and our findings reported here, we suggest that mimicking TNFα-mediated inflammation [20] in prostate cells results in a significant increase in pAkt(S473), which consequently inhibits GSK3β kinase activity by increasing the phosphorylation from (S9) residue (Figure 1E). Furthermore, the decrease in β-catenin(S33) phosphorylation implies that either proteosomal degradation is activated and β-catenin(S33) is depleted by ubiquitination dependent proteosomal machinery, or there can be an increase in the stabilizing phosphorylation of β-catenin(S552), which suppresses the S33 phosphorylation (Figure 1E) by enhanced Akt activity. As the majority of the total β-catenin localizes at the cell membrane, and associates with E-cadherin at adherent junctions, whereas the total β-catenin level does not change, we suggest that CM-mediated Akt activation abrogates the E-cadherin and β-catenin association at plasma membrane localization. This hypothesis is confirmed by the increasing ratios of nuclear/cytoplasmic and cytoplasmic/membrane localization of β-catenin in our studies and the schema was drawn accordingly (Figure 7). Moreover, in a previous study, Lamb et. al. [36] have demonstrated that blocking E-cadherin leads to a decrease in AKT activation. This data suggests that cell-cell adhesion is mediated by E-cadherin interaction that promotes the secretory-like cell survival through PI3K signaling. Hence, the putative mechanism can be a crosstalk between Akt signaling and E-cadherin localization, and its expression does not change in CM, but with ectopic NKX3.1 expression, E-cadherin localization to cell membrane might be facilitated through EGFR pathway. Ascertain the putative mechanism requires further studies.

Bottom Line: Nevertheless, ectopic expression of NKX3.1, which is degraded upon proinflammatory cytokine exposure in inflammation, was found to induce the degradation of β-catenin by inhibiting Akt(S473) phosphorylation, therefore, partially rescued the disrupted β-catenin-E-cadherin interaction as well as the cell migration in LNCaP cells upon cytokine exposure.As, the disrupted localization of β-catenin at the cell membrane as well as increased Akt(S308) priming phosphorylation was observed in human prostate tissues with prostatic inflammatory atrophy (PIA), high-grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma lesions correlated with loss of NKX3.1 expression.Thus, the data indicate that the β-catenin signaling; consequently sub-cellular localization is deregulated in inflammation, associates with prostatic atrophy and PIN pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, Cancer Biology Laboratory, Faculty of Engineering, Ege University, Bornova, Izmir, Turkey; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey.

ABSTRACT
Inflammation-induced carcinogenesis is associated with increased proliferation and migration/invasion of various types of tumor cells. In this study, altered β-catenin signaling upon TNFα exposure, and relation to loss of function of the tumor suppressor NKX3.1 was examined in prostate cancer cells. We used an in vitro prostate inflammation model to demonstrate altered sub-cellular localization of β-catenin following increased phosphorylation of Akt(S473) and GSK3β(S9). Consistently, we observed that subsequent increase in β-catenin transactivation enhanced c-myc, cyclin D1 and MMP2 expressions. Consequently, it was also observed that the β-catenin-E-cadherin association at the plasma membrane was disrupted during acute cytokine exposure. Additionally, it was demonstrated that disrupting cell-cell interactions led to increased migration of LNCaP cells in real-time migration assay. Nevertheless, ectopic expression of NKX3.1, which is degraded upon proinflammatory cytokine exposure in inflammation, was found to induce the degradation of β-catenin by inhibiting Akt(S473) phosphorylation, therefore, partially rescued the disrupted β-catenin-E-cadherin interaction as well as the cell migration in LNCaP cells upon cytokine exposure. As, the disrupted localization of β-catenin at the cell membrane as well as increased Akt(S308) priming phosphorylation was observed in human prostate tissues with prostatic inflammatory atrophy (PIA), high-grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma lesions correlated with loss of NKX3.1 expression. Thus, the data indicate that the β-catenin signaling; consequently sub-cellular localization is deregulated in inflammation, associates with prostatic atrophy and PIN pathology.

Show MeSH
Related in: MedlinePlus