Survivin-3B promotes chemoresistance and immune escape by inhibiting caspase-8 and -6 in cancer cells

Abstract

Survivin-3B (S-3B), an alternative splice isoform of survivin, plays a key role in tumorigenesis. S-3B promotes the escape of malignant cells from immune recognition by blocking the cytotoxicity of natural killer (NK) cells. Such an effect reflects the ability of S-3B to interfere with the assembly of the so-called "death-inducing signaling complex" upon the interaction of FAS with its ligand (FASL). S-3B also inhibits the activation of caspase-6, thus increasing the resistance of neoplastic cells to granzyme B and various chemotherapeutics.

Keywords: caspase-6; caspase-8; survivin-3B; treatment response; tumor escape; tumorigenesis.

Figure 1. Involvement of survivin-3B in cancer initiation, progression, and dissemination. The defects in alternative splicing that normally accompany oncogenesis can result in the production of survivin-3B (S-3B). Pre-malignant cells are normally detected by the immune system, in particular by natural killer (NK) cells. Upon such a recognition, activated NK cells attempt to eliminate target cells by triggering FAS-dependent cell death and by secreting granzyme B. However, S-3B inhibits both the extrinsic and the intrinsic pathways of apoptosis. In this way, pre-malignant cells can escape elimination by the immune system and generate neoplastic lesions. In addition, S-3B inhibits the apoptotic response of cancer cells to chemotherapy and perhaps favors their metastatic dissemination. Dashed lines summarize several events occurring upstream of the represented process.