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

被引：79

作者：

Rasul, S. ^{[1
]}

Balasubramanian, R. ^{[1
]}

Filipovic, A. ^{[1
]}

Slade, M. J. ^{[1
]}

Yaguee, E. ^{[1
]}

Coombes, R. C. ^{[1
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Dept Oncol, Div Surg Oncol Reprod Biol & Anaesthet, London W12 0NN, England

来源：

BRITISH JOURNAL OF CANCER | 2009年 / 100卷 / 12期

关键词：

gamma-secretase; breast cancer; Notch; cell cycle arrest; proteasome; apoptosis; INTRACELLULAR DOMAIN; P-GLYCOPROTEIN; SIGNALING PATHWAY; CARCINOMA-CELLS; NOTCH; EXPRESSION; ACTIVATION; RECEPTOR; CLEAVAGE; PROLIFERATION;

D O I：

10.1038/sj.bjc.6605034

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

gamma-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 gamma-secretase inhibitors (GSIs) in breast cancer cells. One inhibitor (GSI1) was lethal to breast cancer cell lines at concentrations of 2 mu M 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 gamma-secretase activity and downregulation of the Notch signalling pathway with no effects on expression of the g-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 g-secretase inhibitor GSI1 has a complex mode of action to inhibit breast cancer cell survival and may represent a novel therapy in breast cancer. British Journal of Cancer (2009) 100, 1879-1888. doi: 10.1038/sj.bjc.6605034 www.bjcancer.com (C) 2009 Cancer Research UK

引用

页码：1879 / 1888

页数：10

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