API5 Confers Tumoral Immune Escape through FGF2-Dependent Cell Survival Pathway

Abstract

Identifying immune escape mechanisms used by tumors may define strategies to sensitize them to immunotherapies to which they are otherwise resistant. In this study, we show that the anti-apoptotic gene API5 acts as an immune escape gene in tumors by rendering them resistant to apoptosis triggered by tumor antigen-specific T cells. Its RNAi-mediated silencing in tumor cells expressing high levels of API5 restored antigen-specific immune sensitivity. Conversely, introducing API5 into API5low cells conferred immune resistance. Mechanistic investigations revealed that API5 mediated resistance by upregulating FGF2 signaling through a FGFR1/PKCδ/ERK effector pathway that triggered degradation of the pro-apoptotic molecule BIM. Blockade of FGF2, PKCδ or ERK phenocopied the effect of API5 silencing in tumor cells expressing high levels of API5, to either murine or human antigen-specific T cells. Our results identify a novel mechanism of immune escape that can be inhibited to potentiate the efficacy of targeted active immunotherapies.

Identifying suitable reference genes for gene expression analysis in developing skeletal muscle in pigs

“…The results analyzed by three different algorithms (NormFinder, BestKeeper, and geNorm) showed that apoptosis inhibitor 5 ( API5 ) was the best candidate reference gene for normalizing target gene expression in developing skeletal muscle across the tested prenatal and postnatal periods. API5 is highly conserved across species from microorganisms to plants and animals (Li et al, 2011; Mayank et al, 2015; Noh et al, 2014). AP15 has an important role in negative regulation of apoptotic processes in fibroblasts (Kim et al, 2000; Noh et al, 2014).…”

“…API5 is highly conserved across species from microorganisms to plants and animals (Li et al, 2011; Mayank et al, 2015; Noh et al, 2014). AP15 has an important role in negative regulation of apoptotic processes in fibroblasts (Kim et al, 2000; Noh et al, 2014). This gene encodes an inhibitory protein that prevents apoptosis after growth factor deprivation.…”

“…The API5 protein suppresses apoptosis induced by the transcription factor E2F1, and interacts with and negatively regulates Acinus, a nuclear factor involved in apoptotic DNA fragmentation. The API5 gene is involved in many human diseases including diabetes and cancers (Cho et al, 2014; Noh et al, 2014; Peng et al, 2015; Ramdas et al, 2011). However, API5 has not been reported to be involved in skeletal muscle development.…”

Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma

“…Considering the aggressive nature of the defects leading to eBL development, downregulated miR-10a-5p could also promote the hyperactivation of API5 (apoptosis inhibitor 5), an apoptosis inhibitory protein, which renders tumor cells resistant to T cell initiated apoptosis (Noh et al, 2014). API5 has been shown to impair the cytotoxic effect induced by chemotherapeutic drugs (Faye and Poyet, 2010), while miR-10a-5p confers post-transcriptional regulation of API5 gene (Karginov and Hannon, 2013).…”

Computer simulations of protein–membrane systems

“…353 Among them, the basic fibroblast growth factor 2 (FGF2), apart from carrying out its normal functions, also mediates tumor-induced angiogenesis and inhibits tumor cell apoptosis. [354][355][356] Further, the lack of a signal peptide makes FGF2 unique among its family members, and it is secreted into the extracellular space by an unconventional route, independent of ER/Golgi pathway. [357][358][359] In vitro studies suggest that the unconventional FGF2 translocation takes place through initial interactions with the inner leaflet PI(4,5)P 2 lipids.…”