title: YM155 sensitizes triple-negative breast cancer to membrane-bound TRAIL through p38 MAPK- and CHOP-mediated DR5 upregulation.
abstract: Because available treatments have limited efficacy in triple-negative breast cancer (TNBC), the identification of new therapeutic strategies to improve patients' outcome is urgently needed. In our study, we investigated the effects of the administration of the small molecule selective survivin suppressant YM155, alone or in association with CD34+ cells transduced with a replication-deficient adenovirus encoding the human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene (CD34-TRAIL+ cells), in three TNBC cell models. YM155 exposure significantly impaired TNBC cell growth and selectively modulated survivin expression at both mRNA and protein level. In addition, co-culturing YM155-treated TNBC cells with CD34-TRAIL+ cells resulted in markedly increased cytotoxic effect and apoptotic response in comparison with single treatments. Such a chemosensitizing effect was observed only in TNBC cells inherently expressing DR5 and relied on the ability of YM155 to upregulate DR5 expression through a p38 MAPK- and CHOP-dependent mechanism. YM155/CD34-TRAIL+ combination also showed a significant inhibitory effect on the growth of DR5-expressing TNBC cells following xenotransplantation into NOD/SCID mice, in the absence of toxicity. Overall, our data (i) provide, for the first time, evidence that YM155 sensitizes TNBC cells to CD34-TRAIL+ cells-induced apoptosis by a mechanism involving the downregulation of survivin and the simultaneous p38 MAPK- and CHOP-mediated upregulation of DR5, and (ii) suggest the combination of YM155 with TRAIL-armed CD34+ progenitor cells as a promising therapeutic option for patients with TNBC expressing DR5.
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Pennati
authors.forename: Stefania
authors.initials: S
authors.lastname: Sbarra
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Alessia
authors.initials: A
authors.lastname: Lopergolo
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Locatelli
authors.forename: Elisa
authors.initials: E
authors.lastname: Campi
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Daidone
authors.forename: Carmelo
authors.initials: C
authors.lastname: Carlo-Stella
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Gianni
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009285:Naphthoquinones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; D048051:p38 Mitogen-Activated Protein Kinases; C523798:sepantronium
keywords: TRAIL; YM155; death receptors; survivin; triple-negative breast cancer