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Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells

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Title: Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells
Authors: Rasul, S
Balasubramanian, R
Filipovic, A
Slade, MJ
Yaguee, E
Coombes, RC
Item Type: Journal Article
Abstract: γ-Secretase activity is vital for the transmembrane cleavage of Notch receptors and the subsequent migration of their intracellular domains to the nucleus. Notch overexpression has been associated with breast, colon, cervical and prostate cancers. We tested the effect of three different γ-secretase inhibitors (GSIs) in breast cancer cells. One inhibitor (GSI1) was lethal to breast cancer cell lines at concentrations of 2 μM and above but had a minimal effect on the non-malignant breast lines. GSI1 was also cytotoxic for a wide variety of cancer cell lines in the NCI60 cell screen. GSI1 treatment resulted in a marked decrease in γ-secretase activity and downregulation of the Notch signalling pathway with no effects on expression of the γ-secretase components or ligands. Flow cytometric and western blot analyses indicated that GSI1 induces a G2/M arrest leading to apoptosis, through downregulation of Bcl-2, Bax and Bcl-XL. GSI1 also inhibited proteasome activity. Thus, the γ-secretase inhibitor GSI1 has a complex mode of action to inhibit breast cancer cell survival and may represent a novel therapy in breast cancer.
Issue Date: 16-Jun-2009
Date of Acceptance: 18-Mar-2009
URI: http://hdl.handle.net/10044/1/69168
DOI: https://dx.doi.org/10.1038/sj.bjc.6605034
ISSN: 0007-0920
Publisher: Springer Nature [academic journals on nature.com]
Start Page: 1879
End Page: 1888
Journal / Book Title: British Journal of Cancer
Volume: 100
Issue: 12
Copyright Statement: © 2009 Cancer Research UK. From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
gamma-secretase
breast cancer
Notch
cell cycle arrest
proteasome
apoptosis
INTRACELLULAR DOMAIN
P-GLYCOPROTEIN
SIGNALING PATHWAY
CARCINOMA-CELLS
NOTCH
EXPRESSION
ACTIVATION
RECEPTOR
CLEAVAGE
PROLIFERATION
Amyloid Precursor Protein Secretases
Apoptosis
Breast Neoplasms
Cell Division
Cell Proliferation
Enzyme Inhibitors
Female
Flow Cytometry
G2 Phase
Humans
Proto-Oncogene Proteins c-bcl-2
RNA, Messenger
Receptors, Notch
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
bcl-2-Associated X Protein
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
Publication Status: Published
Online Publication Date: 2009-06-09
Appears in Collections:Department of Surgery and Cancer