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  • 1
    Online Resource
    Online Resource
    Protein kinase C regulates Twist1 expression via NF-κB in prostate cancer
    Bioscientifica ; 2017
    In:  Endocrine-Related Cancer Vol. 24, No. 4 ( 2017-04), p. 171-180
    Details
    In: Endocrine-Related Cancer, Bioscientifica, Vol. 24, No. 4 ( 2017-04), p. 171-180
    Abstract: The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that protein kinase C (PKC) activation followed by Twist1 and androgen receptor (AR) induction played a critical role in castration resistance, but the precise molecular mechanism remains unknown. This study aimed to elucidate the relevant molecular mechanism, focusing on NF-κB transcription factor. We examined the activity of NF-κB after PKC inhibition, and the expression of Twist1 and AR after inhibition of NF-κB in human prostate cancer cells. We also investigated the status of PKC/NF-κB after inhibition of AR signaling in cells resistant to hormonal therapy. As a result, inhibition of PKC signaling using knockdown and small-molecule inhibition of PKC suppressed RelA activity, while blocking NF-κB suppressed Twist1 and AR expression. Conversely, inhibition of AR signaling by androgen depletion and the novel antiandrogen enzalutamide induced PKC and RelA activation, resulting in Twist1/AR induction at the transcript level. Moreover, inhibition of NF-κB signaling prevented enzalutamide-induced Twist1 and AR induction. Finally, NF-κB was activated in both castration-resistant and enzalutamide-resistant cells. In conclusion, NF-κB signaling was responsible for Twist1 upregulation by PKC in response to AR inhibition, resulting in aberrant activation of AR. NF-κB signaling thus appears to play a critical role in promoting both castration resistance and enzalutamide resistance in PKC/Twist1 signaling in prostate cancer.
    Type of Medium: Online Resource
    ISSN: 1351-0088 , 1479-6821
    URL: Article
    DOI: 10.1530/ERC-16-0384
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2017
    detail.hit.zdb_id: 2010895-3
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  • 2
    Online Resource
    Online Resource
    Y-box binding protein-1 promotes castration-resistant prostate cancer growth via androgen receptor expression
    Bioscientifica ; 2011
    In:  Endocrine-Related Cancer Vol. 18, No. 4 ( 2011-06-7), p. 505-517
    Details
    In: Endocrine-Related Cancer, Bioscientifica, Vol. 18, No. 4 ( 2011-06-7), p. 505-517
    Abstract: The androgen receptor (AR) is well known to play a central role in the pathogenesis of prostate cancer (PCa). In several studies, AR was overexpressed in castration-resistant PCa (CRPC). However, the mechanism of AR overexpression in CRPC is not fully elucidated. Y-box binding protein-1 (YB-1) is a pleiotropic transcription factor that is upregulated in CPRC. We aimed to elucidate the role of YB-1 in castration resistance of PCa and identify therapeutic potential of targeting YB-1. Using immunohistochemistry, we found that nuclear YB-1 expression significantly correlated with the Gleason score and AR expression in PCa tissues. In PCa cells, YB-1 regulated AR expression at the transcriptional level. Furthermore, YB-1 expression and nuclear localization were upregulated in CRPC cells. Overexpression of AR, as well as YB-1, conferred castration-resistant growth in LNCaP and 22Rv1 cells. Conversely, knocking down YB-1 resulted in suppressed cell growth and induced apoptosis, which was more efficient than knocking down AR in LNCaP cells. In other types of PCa cells, such as CRPC cells, knocking down YB-1 resulted in a significant reduction of cell growth. In conclusion, these findings suggested that YB-1 induces castration resistance in androgen-dependent PCa cells via AR expression. Thus, YB-1 may be a promising therapeutic target for PCa, as well as CRPC.
    Type of Medium: Online Resource
    ISSN: 1351-0088 , 1479-6821
    URL: Article
    DOI: 10.1530/ERC-11-0017
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2011
    detail.hit.zdb_id: 2010895-3
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  • 3
    Online Resource
    Online Resource
    PMA induces androgen receptor downregulation and cellular apoptosis in prostate cancer cells
    Bioscientifica ; 2014
    In:  Journal of Molecular Endocrinology Vol. 53, No. 1 ( 2014-04-29), p. 31-41
    Details
    In: Journal of Molecular Endocrinology, Bioscientifica, Vol. 53, No. 1 ( 2014-04-29), p. 31-41
    Abstract: Phorbol 12-myristate 13-acetate (PMA) induces cellular apoptosis in prostate cancer cells, the growth of which is governed by androgen/androgen receptor (AR) signaling, but the mechanism by which PMA exerts this effect remains unknown. Therefore, in this study, we investigated the mechanistic action of PMA in prostate cancer cells with regard to AR. We showed that PMA decreased E2F1 as well as AR expression in androgen-dependent prostate cancer LNCaP cells. Furthermore, PMA activated JNK and p53 signaling, resulting in the induction of cellular apoptosis. In LNCaP cells, androgen deprivation and a novel anti-androgen enzalutamide (MDV3100) augmented cellular apoptosis induced by PMA. Moreover, castration-resistant prostate cancer (CRPC) C4-2 cells were more sensitive to PMA compared with LNCaP cells and were sensitized to PMA by enzalutamide. Finally, the expression of PKC, E2F1, and AR was diminished in PMA-resistant cells, indicating that the gain of independence from PKC, E2F1, and AR functions leads to PMA resistance. In conclusion, PMA exerted its anti-cancer effects via the activation of pro-apoptotic JNK/p53 and inhibition of pro-proliferative E2F1/AR in prostate cancer cells including CRPC cells. The therapeutic effects of PMA were augmented by androgen deletion and enzalutamide in androgen-dependent prostate cancer cells, as well as by enzalutamide in castration-resistant cells. Taken together, PMA derivatives may be promising therapeutic agents for treating prostate cancer patients including CRPC patients.
    Type of Medium: Online Resource
    ISSN: 0952-5041 , 1479-6813
    URL: Article
    DOI: 10.1530/JME-13-0303
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2014
    detail.hit.zdb_id: 1478171-2
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  • 4
    Online Resource
    Online Resource
    Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer
    Bioscientifica ; 2015
    In:  Endocrine-Related Cancer Vol. 22, No. 6 ( 2015-08-26), p. 889-900
    Details
    In: Endocrine-Related Cancer, Bioscientifica, Vol. 22, No. 6 ( 2015-08-26), p. 889-900
    Abstract: Although invasive and metastatic progression via the epithelial-mesenchymal transition (EMT) and acquisition of resistance to castration are both critical steps in prostate cancer, the molecular mechanism of this interaction remains unclear. In this study, we aimed to elucidate the interaction of signaling between castration resistance and EMT, and to apply this information to the development of a novel therapeutic concept using transforming growth factor-β (TGF-β) inhibitor SB525334 combined with androgen-deprivation therapy against prostate cancer using an in vivo model. This study revealed that an EMT inducer (TGF-β) induced full-length androgen receptor (AR) and AR variant expression. In addition, a highly invasive clone showed augmented full-length AR and AR variant expression as well as acquisition of castration resistance. Conversely, full-length AR and AR as well as Twist1 and mesenchymal molecules variant expression were up-regulated in castration-resistant LNCaP xenograft. Finally, TGF-β inhibitor suppressed Twist1 and AR expression as well as prostate cancer growth combined with castration. Taken together, these results demonstrate that Twist1/AR signaling was augmented in castration resistant as well as mesenchymal-phenotype prostate cancer, indicating the molecular mechanism of mutual and functional crosstalk between EMT and castration resistance, which may play a crucial role in prostate carcinogenesis and progression.
    Type of Medium: Online Resource
    ISSN: 1351-0088 , 1479-6821
    URL: Article
    DOI: 10.1530/ERC-15-0225
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2015
    detail.hit.zdb_id: 2010895-3
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  • 5
    Online Resource
    Online Resource
    Human heterochromatin protein 1 isoforms regulate androgen receptor signaling in prostate cancer
    Bioscientifica ; 2013
    In:  Journal of Molecular Endocrinology Vol. 50, No. 3 ( 2013-03-27), p. 401-409
    Details
    In: Journal of Molecular Endocrinology, Bioscientifica, Vol. 50, No. 3 ( 2013-03-27), p. 401-409
    Abstract: Androgen receptor (AR) signaling is critical for the tumorigenesis and development of prostate cancer, as well as the progression to castration-resistant prostate cancer. We previously showed that the heterochromatin protein 1 (HP1) β isoform plays a critical role in transactivation of AR signaling as an AR coactivator that promotes prostate cancer cell proliferation. However, the roles of other HP1 isoforms, HP1α and HP1γ, in AR expression and prostate cancer remain unclear. Here, we found that knockdown of HP1γ , but not HP1α , reduced AR expression and cell proliferation by inducing cell cycle arrest at G1 phase in LNCaP cells. Conversely, overexpression of full-length HP1α and its C-terminal deletion mutant increased AR expression and cell growth, whereas overexpression of HP1γ had no effect. Similarly, HP1α overexpression promoted 22Rv1 cell growth, whereas HP1γ knockdown reduced the proliferation of CxR cells, a castration-resistant LNCaP derivative. Taken together, HP1 isoforms distinctly augment AR signaling and cell growth in prostate cancer. Therefore, silencing of HP1β and HP1γ may be a promising therapeutic strategy for treatment of prostate cancer.
    Type of Medium: Online Resource
    ISSN: 0952-5041 , 1479-6813
    URL: Article
    DOI: 10.1530/JME-13-0024
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2013
    detail.hit.zdb_id: 1478171-2
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