Reduced Expression of Annexin A6 Induces Metabolic Reprogramming That Favors Rapid Fatty Acid Oxidation in Triple-Negative Breast Cancer Cells.

Stephen D Williams,Amos M Sakwe

doi:10.3390/cancers14051108

Abstract

Simple SummaryThe expression status of Annexin A6 (AnxA6) has been shown to influence tumor growth, metastasis, and resistance to therapeutic intervention, but the contribution of this tumor suppressor in the metabolic adaptation of basal-like (AnxA6-low) versus mesenchymal-like (AnxA6-high) TNBC subsets remains unclear. The downregulation of AnxA6 in TNBC cells attenuated mitochondrial respiration, glycolytic flux, and cellular ATP production capacity, resulting in a quiescent metabolic phenotype. The overexpression or chronic lapatinib induced the expression of AnxA6 in AnxA6-low TNBC cells and reversed the quiescent phenotype to a more lipogenic/glycolytic phenotype. Interestingly, AnxA6-depletion was associated with rapid fatty acid uptake and oxidation (lypolytic metabolic phenotype) but decreased lipid droplet accumulation. Our data suggest that the expression status of AnxA6 in TNBC cells is associated with distinct metabolic adaptations of basal-like and mesenchymal-like TNBC subsets in response to cellular stress and/or therapeutic intervention.The ability of cancer cells to alter their metabolism is one of the major mechanisms underlying rapid tumor progression and/or therapeutic resistance in solid tumors, including the hard-to-treat triple-negative breast cancer (TNBC) subtype. Here, we assessed the contribution of the tumor suppressor, Annexin A6 (AnxA6), in the metabolic adaptation of basal-like (AnxA6-low) versus mesenchymal-like (AnxA6-high), as well as in lapatinib-resistant TNBC cells. Using model basal-like and mesenchymal-like TNBC cell lines, we show that TNBC cells also exhibit metabolic heterogeneity. The downregulation of AnxA6 in TNBC cells generally attenuated mitochondrial respiration, glycolytic flux, and cellular ATP production capacity resulting in a quiescent metabolic phenotype. We also show that AnxA6 depletion in mesenchymal-like TNBC cells was associated with a rapid uptake and mitochondrial fatty acid oxidation and diminished lipid droplet accumulation and altered the lipogenic metabolic phenotype of these cells to a lypolytic metabolic phenotype. The overexpression or chronic lapatinib-induced upregulation of AnxA6 in AnxA6-low TNBC cells reversed the quiescent/lypolytic phenotype to a more lipogenic/glycolytic phenotype with gluconeogenic precursors as additional metabolites. Collectively, these data suggest that the expression status of AnxA6 in TNBC cells underlies distinct metabolic adaptations of basal-like and mesenchymal-like TNBC subsets in response to cellular stress and/or therapeutic intervention and suggest AnxA6 as a biomarker for metabolic subtyping of TNBC subsets.

Highlights

Triple negative breast cancer (TNBC), which accounts for up to 17% of all breast cancer cases in the United States [1], disproportionately affects premenopausal African American and Hispanic women [1,2,3,4,5,6,7]
We have previously shown that the downregulation of Annexin A6 (AnxA6) in TNBC cell lines led to increased cell proliferation, reduced cell motility, rapid growth of xenograft tumors, and was associated with poor overall survival of basal-like TNBC patients [34,35]
In our quest to better understand the basis for these conspicuous differences in TNBC cellular metabolic phenotypes, we hypothesized that the expression status of AnxA6 affects cellular bioenergetics and the metabolic capacity in the phenotypically-distinct basal-like and mesenchymal-like TNBC cells

Summary

Introduction

Triple negative breast cancer (TNBC), which accounts for up to 17% of all breast cancer cases in the United States [1], disproportionately affects premenopausal African American and Hispanic women [1,2,3,4,5,6,7]. Up to 70% of TNBCs express amplified levels of epidermal growth factor receptor (EGFR), targeting the receptor with tyrosine kinase inhibitors (TKIs) and/or therapeutic monoclonal antibodies even in combination with chemotherapy [10,11,12,13] has been met with dismal patient responses and frequent relapse and metastasis [14,15,16,17] This poor therapeutic response of TNBC may be due to the well described molecular heterogeneity of the TNBC tumors and phenotypic diversity that is depicted by the existence of basal-like (BSL) and mesenchymallike (MES) TNBC subsets [18,19,20,21,22,23]. Our understanding of the metabolic dependencies of the more aggressive BSL-TNBCs remains limited

Methods

Results

Discussion

Conclusion