NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells Molecular Bases of Disease

In this study using RNA-Seq and bioinformatics analyses, we observed that NOTCH signaling is a deregulated pathway in enzalutamide-resistant cells. NOTCH2 and c-MYC gene expression positively correlated with AR expression in samples from patient with hormone refractory disease in which AR expression levels correspond to those typically observed in enzalutamide resistance. Cleaved NOTCH1, HES1 (Hes family BHLH transcription factor 1), and c-MYC protein expression levels are elevated in two enzalutamide-resistant cell lines, MR49F and C4-2R, indicating NOTCH signaling activation. Moreover, inhibition of the overexpressed ADAM metallopeptidase domain 10 (ADAM10) in the resistant cells induces an exclusive reduction in cleaved NOTCH1 expression. Furthermore, exposure of enzalutamide-resistant cells to both PF-03084014 and enzalutamide increased cell death, decreased colony formation ability, and resensitized cells to enzalutamide. Knockdown of NOTCH1 in C4-2R increased enzalutamide sensitivity by decreasing cell proliferation and increasing cleaved PARP expression. In a 22RV1 xenograft model, PF-03084014 and enzalutamide decreased tumor growth through reducing cell proliferation and increasing apoptosis. These results indicate that NOTCH1 signaling may contribute to enzalutamide resistance in prostate cancer, and inhibition of NOTCH signaling can resensitize resistant cells to enzalutamide.
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Cell Biology Source Type: research

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Abstract Cancer of the prostate are cancers in which most incidences are slow growing and in the U.S., a record of 1.2 million new cases of prostate cancer occurred in 2018. The rates of this type of cancer have been increasing in the developing nations. The risk factors for prostate cancer include age, family history, and obesity. It is believed that the rate of prostate cancer is correlated with the Western diet. Various advances in methods of radiotherapy have contributed to lowering morbidity. Therapy for hormone-refractory prostate cancer is making progress, for almost all men with metastases will proceed to ...
Source: Current Topics in Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Top Med Chem Source Type: research
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Source: World Journal of Urology - Category: Urology & Nephrology Source Type: research
Publication date: Available online 28 August 2019Source: Life SciencesAuthor(s): Pan Bian, Zhongling Dou, Zhaohui Jia, Wensheng Li, Dong PanAbstractDocetaxel is commonly used to treat hormone-refractory prostate cancer (HRPC), but its clinical efficacy is limited by drug resistance, with the molecular mechanisms remaining elusive. The E3 ubiquitin ligase EDD modifies substrate proteins through ubiquitination and is involved in the regulation of cell proliferation and tumorigenesis. However, its role in docetaxel resistance of prostate cancer is unknown. Here, we show that EDD is upregulated in docetaxel-resistant HRPC cell...
Source: Life Sciences - Category: Biology Source Type: research
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Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
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Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research
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Source: Cytotherapy - Category: Cytology Source Type: research
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Source: Journal of Nuclear Medicine - Category: Nuclear Medicine Authors: Tags: Preclinical Probes for Oncology Posters Source Type: research
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Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
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Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
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Source: American Journal of Clinical Oncology - Category: Cancer & Oncology Tags: Original Articles: Genitourinary Source Type: research
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