학술논문
Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells.
Document Type
Journal Article
Author
Source
Subject
*BREAST cancer
*CANCER cells
*CELL lines
*CELL membranes
*CELL nuclei
*APOPTOSIS
*PROTEIN metabolism
*RNA metabolism
*BREAST tumors
*CELL division
*CELL physiology
*CELL receptors
*COMPARATIVE studies
*ENZYME inhibitors
*FLOW cytometry
*RESEARCH methodology
*MEDICAL cooperation
*POLYMERASE chain reaction
*PROTEINS
*PROTEOLYTIC enzymes
*RESEARCH
*RESEARCH funding
*RNA
*EVALUATION research
*REVERSE transcriptase polymerase chain reaction
*CANCER cell culture
*CHEMICAL inhibitors
*PHARMACODYNAMICS
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Language
ISSN
0007-0920
Abstract
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 muM 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 gamma-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 gamma-secretase inhibitor GSI1 has a complex mode of action to inhibit breast cancer cell survival and may represent a novel therapy in breast cancer. [ABSTRACT FROM AUTHOR]