Reduced Expression of Annexin A6 Induces Metabolic Reprogramming That Favors Rapid Fatty Acid Oxidation in
Stephen D Williams1, Amos M Sakwe1
1Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN 37208, USA.
Abstract:
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.
Insights
Annexin A6 (AnxA6) impacts triple-negative breast cancer (TNBC) cell metabolism. AnxA6 levels dictate metabolic phenotypes, influencing tumor progression and therapeutic resistance in TNBC subtypes.
Area of Science:
- Cancer Biology
- Metabolic Regulation
- Tumor Microenvironment
Background:
- Metabolic adaptation is crucial for tumor progression and therapeutic resistance in solid tumors.
- Triple-negative breast cancer (TNBC) is a challenging subtype with significant unmet clinical needs.
- Tumor suppressor Annexin A6 (AnxA6) role in TNBC metabolic heterogeneity is not well understood.
Purpose of the Study:
- To investigate the role of Annexin A6 (AnxA6) in the metabolic adaptation of different triple-negative breast cancer (TNBC) subtypes.
- To determine how AnxA6 expression influences metabolic phenotypes in basal-like and mesenchymal-like TNBC cells.
- To explore the impact of AnxA6 on lapatinib resistance and metabolic plasticity in TNBC.
Main Methods:
- Utilized model basal-like and mesenchymal-like TNBC cell lines to study metabolic heterogeneity.
- Assessed mitochondrial respiration, glycolytic flux, ATP production, and lipid metabolism.
- Manipulated AnxA6 expression (downregulation and overexpression) and evaluated metabolic consequences.
Main Results:
- AnxA6 downregulation in TNBC cells led to attenuated respiration, glycolysis, and ATP production, creating a quiescent metabolic phenotype.
- AnxA6 depletion in mesenchymal-like TNBC cells promoted fatty acid oxidation and shifted cells towards a lipolytic phenotype.
- AnxA6 overexpression or lapatinib-induced upregulation in AnxA6-low TNBC cells reversed phenotypes to lipogenic/glycolytic with gluconeogenic precursors.
Conclusions:
- AnxA6 expression status is a key determinant of distinct metabolic adaptations in basal-like and mesenchymal-like TNBC subsets.
- These metabolic shifts are influenced by cellular stress and therapeutic interventions.
- AnxA6 serves as a potential biomarker for metabolic subtyping of TNBC, aiding in understanding treatment resistance.
