Notch is a family of transmembrane receptors whose activation through proteolytic cleavage by γ-
secretase targets genes which participate in cell development, differentiation and
tumorigenesis. Notch signaling is constitutively activated in various
cancers, including
breast cancer and its upregulation is usually related with poor clinical outcomes. Therefore, targeting Notch signaling with γ-
secretase inhibitors (GSIs) is considered a promising strategy for
cancer treatment. We report that the γ-
secretase inhibitor-I (GSI-I) sensitizes human
breast cancer cells to apoptosis mediated by
tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL). The antiproliferative GSI-I/TRAIL synergism was stronger in ER-negative MDA-MB-231
breast cancer cells compared with ER-positive MCF-7 cells. In MDA-MB-231 cells, GSI-I treatment induced upregulation of DR4 and DR5
TRAIL receptors. This effect seemed to be related to the activation of the
transcription factor AP1 that was a consequence of Notch inhibition, as demonstrated by Notch-1 silencing experiments. Combined treatment induced loss of the mitochondrial transmembrane potential and activation of
caspases. GSI-I alone and/or GSI-I/TRAIL combination also induced a significant decrease in the levels of some survival factors (
survivin, c-IAP-2, Bcl-xL, BimEL and pAKT) and upregulation of pro-apoptotic factors BimL, BimS and Noxa, enhancing the cytotoxic potential of the two drugs. Taken together, these results indicate for the first time that GSI-I/TRAIL combination could represent a novel and potentially effective tool for
breast cancer treatment.