Survivin-3B potentiates immune escape in cancer but also inhibits the toxicity of cancer chemotherapy

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la survivine 3B dans la résistance à une chimiothérapie

Résumé en anglais

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 pro-caspase-8, inhibiting DISC formation in response to Fas/Fas ligand interaction. We found that S-3B overexpression also mediated resistant to cancer chemotherapy, in this case through interactions with pro-caspase-6. S-3B binding to procaspase-6 inhibited its activation in spite of mitochondrion 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 aa region as responsible for the pro-cancerous properties of survivin proteins. Taken together, our results defined survivin-3B as an important functional actor in tumor formation and treatment resistance.