Ketomimetic Nutrients Trigger a Dual Metabolic Defense in Breast Cancer Cells.
Mohini KamraYuan-I ChenPaula DelgadoErin H SeeleyStephanie K SeidlitsHsin-Chin YehAmy BrockSapun H ParekhPublished in: bioRxiv : the preprint server for biology (2024)
While the triggers for the metastatic transformation of breast cancer (BC) cells remain unknown, recent evidence suggests that intrinsic cellular metabolism could be a crucial driver of migratory disposition and chemoresistance. Aiming to decode the molecular mechanisms involved in BC cell metabolic maneuvering, we study how a ketomimetic (ketone body rich, low glucose) medium affects Doxorubicin (DOX) susceptibility and invasive disposition of BC cells. We quantified glycocalyx sialylation and found an inverse correlation with DOX-induced cytotoxicity and DOX internalization. These measurements were coupled with single-cell metabolic imaging, bulk migration studies, along with transcriptomic and metabolomic analyses. Our findings revealed that a ketomimetic medium enhances chemoresistance and invasive disposition of BC cells via two main oncogenic pathways: hypersialylation and lipid synthesis. We propose that the crosstalk between these pathways, juxtaposed at the synthesis of the glycan precursor UDP-GlcNAc, furthers advancement of a metastatic phenotype in BC cells under ketomimetic conditions.
Keyphrases
- induced apoptosis
- single cell
- cell cycle arrest
- squamous cell carcinoma
- rna seq
- breast cancer cells
- high resolution
- type diabetes
- signaling pathway
- oxidative stress
- drug delivery
- cell death
- adipose tissue
- cell proliferation
- metabolic syndrome
- transcription factor
- photodynamic therapy
- blood pressure
- young adults
- endothelial cells
- weight loss
- stress induced