Survivin-3B potentiates immune escape in cancer but also inhibits the toxicity of cancer chemotherapy.
Cancer Res
; 73(17): 5391-401, 2013 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-23856250
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Células Matadoras Naturais
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Proteínas Inibidoras de Apoptose
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Fluoruracila
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Neoplasias
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article