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


The cover for issue 61 of Oncotarget features Figure 4, "The influence of stress conditions on API-5 expression and inhibition," by Bousquet, et al.

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 and the other resistant to most tested drugs.

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.

Figure 4: The influence of stress conditions on API-5 expression and inhibition. (A)

Figure 4: The influence of stress conditions on API-5 expression and inhibition. (A) Hypoxia CAIX immunostaining on XBC-R and XBC-S (n = 5 for each). CAIX labelling and necrotic areas were detected at a magnification of 200 (top panel) and 400 (bottom panel). (B, C) API-5 expression in HMEC cells and the effect of anti-API-5 peptide under hypoxia and metabolic stress conditions respectively. API-5 expression showed an increase after 12 h and 24 h of hypoxia and metabolic stress respectively. The effect of anti-API-5 peptide was more efficient under stress conditions on HMEC cell viability.

Dr. Melanie Di Benedetto and Dr. Guilhem Bousquet said, "Apoptosis Inhibitor-5 (API-5) also called Anti-Apoptosis Clone 11 (AAC-11) is a 58-kDa nuclear protein highly conserved across species."

API-5 was originally identified as an anti-apoptotic protein in mouse fibroblasts and in human cervical carcinoma cell lines, in which API-5 significantly enhanced cell survival after serum deprivation or ultraviolet sensitization.

In vitro, a decrease in API-5 expression sensitized human cancer cell lines to apoptosis, and increased their sensitivity to anticancer drugs.

In human osteocarcinoma cells, API-5 promotes survival through the inhibition of an E2 promoter-binding factor, and the integrity of the leucine zipper domain is required for the anti-apoptotic functions of API-5.

Previous authors engineered an anti-API5 peptide composed of the LZ domain fused with the Antennapedia/Penetrating protein domain since the integrity of this domain is essential for the function of API-5. This LZ peptide is able to penetrate cells in vitro, and to cancel the API-5/acinus interaction.

In this pre-clinical study, the authors studied the expression of API-5 in patients with chemotherapy-resistant TNBC and the inhibition of API-5 in a resistant TNBC xenograft model.

The Benedetto/Bousquet Research Team concluded that Hypoxia is associated with drug resistance and they have previously demonstrated a link between cancer stem-cells, hypoxic niches and resistance to sunitinib in renal cell carcinoma.

In vivo, hypoxia has been shown to induce resistance to apoptosis in human cervical cancer cell lines through a selection of p53-mutated cells.

Full text - https://doi.org/10.18632/oncotarget.27312

Correspondence to - Melanie Di Benedetto - [email protected] and Guilhem Bousquet - [email protected]

Keywords - triple-negative breast cancer, chemotherapy resistance, apoptosis-inhibitor-5, peptide, anti-angiogenic therapy

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