Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Stoyanova, Tanya; Riedinger, Mireille; Lin, Shu Rung; Faltermeier, Claire; Smith, Bryan; Zhang, Kelvin X.; Going, Catherine C.; Goldstein, Andrew S.; Lee, John K.; Drake, Justin M.; Rice, Meghan A.; Hsu, En‐Chi; Nowroozizadeh, Behdokht; Castor, Brandon; Orellana, Sandra Y.; Blum, Steven M.; Cheng, Donghui; Pienta, Kenneth J.; Reiter, Robert E.; Pitteri, Sharon J.; Huang, Jiaoti; Witte, Owen N.

doi:10.1073/pnas.1614529113

Cited by 47 publications

(39 citation statements)

References 58 publications

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“…Consistent with our findings, a recent study by Stoyanova et al . shows that mouse prostate tumors driven by NICD1 in combination with activation of multiple oncogenic pathways (such as AKT, Myc and Ras) exhibit a castration‐resistant phenotype . Thus, all the experiments support the notion that activation of the Notch signaling induced by ADT enhances the resistance to ADT in PCa.…”

Section: Discussionsupporting

confidence: 62%

Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer

Cui

Wang

Dong

et al. 2018

Intl Journal of Cancer

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Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT-resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In our study, we found upregulated expression of Notch receptors is positive associated with ADT-resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox-induced overexpression of any Notch intracellular domains (NICD1-4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance-associated phospho-p38 and Bcl-2 in LNCaP cells. As a result, pharmacological inhibition of the Notch pathway using γ-secretase inhibitor (GSI), DAPT, downregulated both phospho-p38 and Bcl-2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa.

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Section: Discussionsupporting

confidence: 62%

Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer

Cui

Wang

Dong

et al. 2018

Intl Journal of Cancer

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“…Previous studies have broadly shown that perturbation of the NOTCH1 signalling pathway is linked to the pathogenesis of important lung diseases, in particular, lung cancer and lung lesions [58,59]. However, it has also been proved to play a key role in breast cancer [60,61] and prostate cancer [62]. Additionally, Notch1-IC aberrant overexpression correlates with leukaemia [63] and breast cancer [9,64].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2

Morrugares

Correa-Sáez

Moreno

et al. 2019

Cell. Mol. Life Sci.

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NOTCH proteins constitute a receptor family with a widely conserved role in cell cycle, growing and development regulation. NOTCH1, the best characterised member of this family, regulates the expression of key genes in cell growth and angiogenesis, playing an essential role in cancer development. These observations provide a relevant rationale to propose the inhibition of the intracellular domain of NOTCH1 (Notch1-IC) as a strategy for treating various types of cancer. Notch1-IC stability is mainly controlled by post-translational modifications. FBXW7 ubiquitin E3 ligase-mediated degradation is considered one of the most relevant, being the previous phosphorylation at Thr-2512 residue required. In the present study, we describe for the first time a new regulation mechanism of the NOTCH1 signalling pathway mediated by DYRK2. We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism. We show that DYRK2 regulation by chemotherapeutic agents has a relevant effect on the viability, motility and invasion capacity of cancer cells expressing NOTCH1. In summary, we reveal a novel mechanism of regulation for NOTCH1 which might help us to better understand its role in cancer biology.

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“…50 Recently, one study validated that activation of Notch-1 synergized with multiple pathways in promoting castration resistant prostate cancer. 51 Therefore, identification of precise mechanisms that regulate EMT process would likely be useful for exploring novel therapeutic approaches for the treatment of human cancers. It has been reported that EMT is associated with CSCs in human cancers.…”

Section: Discussionmentioning

confidence: 99%

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

et al. 2017

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Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Cited by 47 publications

References 58 publications

Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer

Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer

Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

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