Higher Glucose Enhances Breast Cancer Cell Aggressiveness

Abstract

Cancer cells overexpress several transcription factors and motor proteins, such as NFkB and kinesin, to accommodate their high energy demand as well as migratory needs via enhanced glycolysis. We hypothesize that high glucose drives cancer progression and cell aggressiveness by decreasing actin expression, increasing NFkB, and kinesin expressions, and by activating Epithelial Mesenchymal Transition (EMT). Using lowly metastatic MCF-7 and highly metastatic MDA-MB231 (MB231) breast cancer cells – highly incident cancer types – we establish how glucose metabolism regulates actin and the biochemical changes that lead to alterations of cell mechanical properties. We find that higher glucose (15 and 30 mM) increases glycolytic enzymes, glucose uptake, migration speed, kinesin, Ki-67, and NFkB expressions (biomarkers), and hybrid EMT phenotype activation (adhesion molecules/cadherins). Downregulation of actin, increased expressions of motor protein and NFkB, and decreased nuclear stiffness – induced by higher glucose – result in a significant increase in the migration speed. Moreover, glucose deprivation using the glucose analog 2-deoxyglucose decreases significantly the migration speed in both cancer cells. Thus, higher glucose promotes a more aggressive phenotype that promises to be a new target for cancer therapy and can help prevent cancer progression in diabetic patients by inhibiting glucose activated mechanisms.

Acknowledgements

We thank Dr. Z.S. Khan for the critical review of our manuscript.

Disclosure Statement

The authors declare no conflict of interest.

Additional information

Funding

This study was supported by startup funds under “President’s Distinguished Chair in Engineering and Science”, Texas Tech University.

Notes on contributors

Julianna M. Santos

J. M. S. and F. H. designed and supervised the project. J.M.S. performed experiments and analyzed data. All authors took part in data interpretation and manuscript preparation. The final manuscript was reviewed and approved by all authors.

Fazle Hussain

J. M. S. and F. H. designed and supervised the project. J.M.S. performed experiments and analyzed data. All authors took part in data interpretation and manuscript preparation. The final manuscript was reviewed and approved by all authors.