High expression of apoptosis protein (Api-5) in chemoresistant triple-negative breast cancers: an innovative target.

Guilhem Bousquet,Anne Janin,Jean-Paul Feugeas,Marc Espié,He Lu,Christophe Leboeuf,Morad El Bouchtaoui,Melanie Di Benedetto,Yuchen Gu

doi:10.18632/oncotarget.27312

Abstract

Anti-apoptotic protein-5 (API-5) is a survival protein interacting with the protein acinus, preventing its cleavage by caspase-3 and thus inhibiting apoptosis. We studied the effect of targeting API-5 in chemoresistant triple negative breast cancers (TNBCs), to reverse chemoresistance.78 TNBC biopsies from patients with different responses to chemotherapy were analysed for API-5 expression before any treatment. Further studies on API-5 expression and inhibition were performed on patient-derived TNBC xenografts, one highly sensitive to chemotherapies (XBC-S) and the other resistant to most tested drugs (XBC-R). In situ assessments of necrosis, cell proliferation, angiogenesis, and apoptosis in response to anti-API-5 peptide were performed on the TNBC xenografts.Clinical analyses of the 78 TNBC biopsies revealed that API-5 was more markedly expressed in endothelial cells before any treatment among patients with chemoresistant TNBC, and this was associated with greater micro-vessel density. A transcriptomic analysis of xenografted tumors showed an involvement of anti-apoptotic genes in the XBC-R model, and API-5 expression was higher in XBC-R endothelial cells. API-5 expression was also correlated with hypoxic stress conditions both in vitro and in vivo. 28 days of anti-API-5 peptide efficiently inhibited the XBC-R xenograft via caspase-3 apoptosis. This inhibition was associated with major inhibition of angiogenesis associated with necrosis and apoptosis.API-5 protein could be a valid therapeutic target in chemoresistant metastatic TNBC.

Highlights

Apoptosis Inhibitor-5 (API-5) called AntiApoptosis Clone 11 (AAC-11) is a 58-kDa nuclear protein highly conserved across species [1]
Since API-5 is involved in resistance to apoptosis [1], we postulated that Triple-negative breast cancer (TNBC) chemoresistance was partly due to tumor resistance to apoptosis and to API-5 expression before any treatment
We found a significantly larger quantity of API-5 (3 times more) in patient-derived TNBC xenografts (XBC)-R compared to patient-derived TNBC xenografts sensitive to tested drugs (XBC-S) xenografts (p < 0.05, Figure 2D)

Summary

Introduction

Apoptosis Inhibitor-5 (API-5) called AntiApoptosis Clone 11 (AAC-11) is a 58-kDa nuclear protein highly conserved across species [1]. API-5 contains two acid domains, three overlapping heptad repeats of hydrophobic amino acid motifs, a leucine zipper (LZ) and a nuclear localization sequence (Supplementary Figure 1A). A decrease in API-5 expression sensitized human cancer cell lines to apoptosis, and increased their sensitivity to anticancer drugs [5,6,7]. API-5 promotes survival through the inhibition of an E2 promoter-binding factor [E2F1] [6], and the integrity of the leucine zipper domain is required for the anti-apoptotic functions of API-5 [7]. API-5 interacts with the protein acinus, preventing its cleavage by caspase-3, and inhibiting the generation of an active P17 fragment, which in turn leads to DNA fragmentation [7], (Supplementary Figure 1B)

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Conclusion