Survivin-3B Potentiates Immune Escape in Cancer but Also Inhibits the Toxicity of Cancer Chemotherapy

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 17; pp. 5391 - 5401
• Main Authors: VEGRAN, Frédérique, MARY, Romain, GIBEAUD, Anne, MIRJOLET, Céline, COLLIN, Bertrand, OUDOT, Alexandra, CHARON-BARRA, Céline, ARNOULD, Laurent, LIZARD-NACOL, Sarab, BOIDOT, Romain
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-09-2013
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Cell Proliferation - drug effects; Female; Fluorouracil - pharmacology; Humans; Immunoprecipitation; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Male; Medical sciences; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred BALB C; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - pathology; Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Repressor Proteins - genetics; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tumors; Chemotherapy; Treatment; Apoptosis inhibitory protein; Toxicity; Inhibitor; Immune evasion; Survivin; Malignant tumor; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-0036

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.