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.
Highlights
Alternative splicing is an important mechanism for the generation of the variety of proteins indispensable for cell functions
We showed that the alternative splice variant S-3B is expressed in tumors from various organs, and that its expression can play a role in tumorigenesis
Its overexpression allowed the growth of nontumorigenic cells in nude mice. We showed that this tumorigenesis capacity was due to the resistance of cancer cells to the toxicity of natural killer (NK) cells
Summary
Alternative splicing is an important mechanism for the generation of the variety of proteins indispensable for cell functions. It is finely regulated to orchestrate cellular processes. Among these defects, alternative splicing misregulation seems to be an important factor. Misregulation of alternative splicing can be observed in cancer cells in the absence of genomic mutations of the genes concerned [1]. Aberrant alternative splicing can give rise to variants that are expressed in cancer tissues and completely absent from normal ones [2]
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