Glucose Deprivation Promotes Cancer Cell Invasion by Varied Expression of EMT Structural Proteins and Regulatory Molecules in MDA-MB-231 Triple-Negative Breast Cancer Cells.

Abstract

Cancer is one of the biggest leading causes of death worldwide. With increased accumulation of environmental factors like radiation and mutagens, causative mutation in the gene pool is increasing day by day in the human population. Metastasis and its resistance to a wide variety of treatments are the reasons which make cancer difficult to treat. It has already been reported that cancer cells introduce smart modifications in their metabolism and signaling pathways which sense changes in cancer microenvironment and help them survive under harsh conditions. The pattern of expression of these signaling molecules and their structural counterparts involved in cancer metastasis need to be investigated. We used different approaches to study the effect of several levels of glucose deprivation on cancer metastasis in the highly resistant breast cancer model cell line MDA-MB-231 grown in high- (25-mM) and low- (5-mM) glucose medium. Microscopic observations have shown that these cancer cells attach to the surface faster in the presence of high-compared to low-glucose concentrations. These observations were supported by varied expression of genes involved in this morphological transition. Under low-glucose concentration, the expression of epithelial-to-mesenchymal transition (EMT) structural proteins and regulatory molecules such as SLUG, ZEB, HIFα1A, STAT3, and VIM was downregulated, whereas expression of G9a (a histone-modifying enzyme, histone methyl transferase inhibitor), Snail, FBPase, MMP13, and PKM2 was upregulated. This resulted in the turning on of resistance mechanisms in MDA-MB-231 cancer cells enabling them to cope with the stressed tumor microenvironments leading to increased cancer invasion and migration. The increased invasion as shown by trans-well study and loose spheroids in 3D spheroid study showed how metastasis is triggered in MDA-MB-231 under glucose starvation. Our data suggests the devastating outcome of nutrient deprivation on cancer progression, which was previously thought to be supportive in cancer control.