title: Survivin-3B potentiates immune escape in cancer but also inhibits the toxicity of cancer chemotherapy.
abstract: Dysregulation in patterns of alternative RNA splicing in cancer cells is emerging as a significant factor in cancer pathophysiology. In this study, we investigated the little known alternative splice isoform survivin-3B (S-3B) that is overexpressed in a tumor-specific manner. Ectopic overexpression of S-3B drove tumorigenesis by facilitating immune escape in a manner associated with resistance to immune cell toxicity. This resistance was mediated by interaction of S-3B with procaspase-8, inhibiting death-inducing signaling complex formation in response to Fas/Fas ligand interaction. We found that S-3B overexpression also mediated resistance to cancer chemotherapy, in this case through interactions with procaspase-6. S-3B binding to procaspase-6 inhibited its activation despite mitochondrial depolarization and caspase-3 activation. When combined with chemotherapy, S-3B targeting in vivo elicited a nearly eradication of tumors. Mechanistic investigations identified a previously unrecognized 7-amino acid region as responsible for the procancerous properties of survivin proteins. Taken together, our results defined S-3B as an important functional actor in tumor formation and treatment resistance.
authors.affiliation: Departments of Tumor Biology and Pathology, Unit of Molecular Biology, Radiotherapy, and Tumor Biology and Pathology, Unit of Pathology, Preclinical Imaging Platform, Centre Georges-François Leclerc, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Végran
authors.forename: Romain
authors.initials: R
authors.lastname: Mary
authors.forename: Anne
authors.initials: A
authors.lastname: Gibeaud
authors.forename: Céline
authors.initials: C
authors.lastname: Mirjolet
authors.forename: Bertrand
authors.initials: B
authors.lastname: Collin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Oudot
authors.forename: Céline
authors.initials: C
authors.lastname: Charon-Barra
authors.forename: Laurent
authors.initials: L
authors.lastname: Arnould
authors.forename: Sarab
authors.initials: S
authors.lastname: Lizard-Nacol
authors.forename: Romain
authors.initials: R
authors.lastname: Boidot
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin
chemical_list: D000964:Antimetabolites, Antineoplastic; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000077022:Survivin; D005472:Fluorouracil