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Published on: November 5, 2021
Glucose-Dependent Cytotoxic Responses in Triple-Negative Breast Cancer: Experimental and Transcriptomic Evidence of
Ishrat Rahman1, Hanan Henidi2, Aisha Alshibli3
1Department of Basic Dental Sciences, College of Dentistry, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
Background:
Triple-negative breast cancer exhibits substantial metabolic heterogeneity, which may influence therapeutic response. This study investigated whether thymoquinone, glabridin, and glycyrrhizic acid exhibit context-dependent cytotoxicity under glucose deprivation and hypoxia, and whether pharmacological inhibition of p38 MAPK modifies these responses.
Methods:
MDA-MB-231 and MCF-7 cells were treated in 2D monolayer culture with thymoquinone, glabridin, glycyrrhizic acid, or doxorubicin under normoxic, glucose-deprived, and hypoxic conditions. Cell viability was assessed by MTT assay, and p38 involvement was explored using SB203580 co-treatment. Selectivity was assessed in MCF-10A cells. Thymoquinone silver-nanoparticles were also evaluated. Bulk TCGA-BRCA basal-like and receptor-defined TNBC cohorts and GSE118389 single-cell TNBC RNA-seq data were analyzed for glycolysis, hypoxia, p38 MAPK, epithelial-mesenchymal transition, stemness, and oxidative-stress signatures.
Results:
In MDA-MB-231 cells, glabridin showed greater cytotoxicity under glucose-replete conditions, whereas glycyrrhizic acid became more cytotoxic during glucose deprivation. The effect of SB203580 varied according to metabolic context, supporting pharmacologically inferred rather than directly validated p38 involvement. Doxorubicin activity was reduced under hypoxia, whereas thymoquinone retained cytotoxic activity. Thymoquinone nanoparticles did not demonstrate clear therapeutic selectivity. Transcriptomic analyses identified a glycolysis-hypoxia relationship. After false-discovery-rate correction, higher p38-related transcriptional activity was associated with increased EMT scores in both bulk TNBC cohorts. Hallmark sensitivity analyses additionally showed higher glycolysis, hypoxia, and EMT scores in p38-high tumors. Single-cell analyses identified similar metabolic-stress and adaptive associations but were exploratory because cells were derived from only six tumors.
Conclusion:
Metabolic context influenced cytotoxic responses in TNBC. These findings support further investigation of microenvironment-adapted therapies, while p38-related mechanisms require direct validation.