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Silencing Notch-1 induces apoptosis and increases the chemosensitivity of prostate cancer cells to docetaxel through Bcl-2 and Bax.

ABSTRACT: Although docetaxel-based chemotherapy is therapeutically efficacious, drug resistance often leads to treatment failure in castration-resistant prostate cancer patients. The Notch signaling pathway plays a key role in prostate development and prostate cancer. We investigated whether silencing Notch-1 has therapeutic potential for the treatment of prostate cancer. To determine this, we performed cell and molecular analyses following the silencing of the Notch-1 gene in PC-3 castration-resistant prostate cancer cells using small interfering RNA. The results demonstrated that silencing the Notch-1 gene effectively inhibits proliferation and induces apoptosis in PC-3 cells. In addition, docetaxel treatment results in decreased proliferation and increased apoptosis in the Notch-1-silenced cells compared to the control PC-3 cells. Docetaxel treatment was also accompanied by an upregulation of Bax and a downregulation of Bcl-2. Thus, Notch-1 silencing downregulates the anti-apoptotic protein Bcl-2, and upregulates the pro-apoptotic protein Bax, which ultimately results in increased sensitivity of PC-3 cells to docetaxel. Taken together, these results suggest that Notch-1 is potentially an effective target for treating castration-resistant prostate cancer.

SUBMITTER: Ye QF

PROVIDER: S-EPMC3362393 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Silencing Notch-1 induces apoptosis and increases the chemosensitivity of prostate cancer cells to docetaxel through Bcl-2 and Bax.

Ye Qi-Fa QF Zhang Yi-Chuan YC Peng Xiao-Qing XQ Long Zhi Z Ming Ying-Zi YZ He Le-Ye LY

Oncology letters 20120117 4

Although docetaxel-based chemotherapy is therapeutically efficacious, drug resistance often leads to treatment failure in castration-resistant prostate cancer patients. The Notch signaling pathway plays a key role in prostate development and prostate cancer. We investigated whether silencing Notch-1 has therapeutic potential for the treatment of prostate cancer. To determine this, we performed cell and molecular analyses following the silencing of the Notch-1 gene in PC-3 castration-resistant pr ...[more]

PMID: 22741011

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Project description:Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110?-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38-/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment-associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK-/- cells and failed to induce apoptosis in BAX-/- and BAX-/-BAK-/- cells, whereas BIM-/- cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.Significance: Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia. Cancer Res; 78(11); 3075-86. ©2018 AACR.

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Silencing Notch-1 induces apoptosis and increases the chemosensitivity of prostate cancer cells to docetaxel through Bcl-2 and Bax.

Publications

Silencing Notch-1 induces apoptosis and increases the chemosensitivity of prostate cancer cells to docetaxel through Bcl-2 and Bax.

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