title: Notch inhibition restores TRAIL-mediated apoptosis via AP1-dependent upregulation of DR4 and DR5 TRAIL receptors in MDA-MB-231 breast cancer cells.
abstract: 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.
authors.affiliation: Dipartimento di Medicina traslazionale, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Portanova
authors.forename: Antonietta
authors.initials: A
authors.lastname: Notaro
authors.forename: Ornella
authors.initials: O
authors.lastname: Pellerito
authors.forename: Selenia
authors.initials: S
authors.lastname: Sabella
authors.forename: Michela
authors.initials: M
authors.lastname: Giuliano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Calvaruso
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016758:Genes, jun / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D051880:Receptors, Notch / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D053829:Amyloid Precursor Protein Secretases