AMPK is required for recovery from metabolic stress induced by ultrasound microbubble treatment
Louis Lo,
Oro Uchenunu,
Roberto J. Botelho,
Costin N. Antonescu,
Raffi Karshafian
Affiliations
Louis Lo
Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada; Graduate Program in Molecular Science, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada
Oro Uchenunu
Faculty of Medicine and Health Sciences, Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada; Department of Physics, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada
Roberto J. Botelho
Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada; Graduate Program in Molecular Science, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada; Corresponding author
Costin N. Antonescu
Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada; Graduate Program in Molecular Science, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada; Corresponding author
Raffi Karshafian
Department of Physics, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada; Institute for Biomedical Engineering, Science and Technology (iBEST), a partnership between Ryerson University and St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada; Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada; Corresponding author
Summary: Ultrasound-stimulated microbubble (USMB) treatment is a promising strategy for cancer therapy. USMB promotes drug delivery by sonoporation and enhanced endocytosis, and also impairs cell viability. However, USMB elicits heterogeneous effects on cell viability, with apparently minimal effects on a subset of cells. This suggests that mechanisms of adaptation following USMB allow some cells to survive and/or proliferate. Herein, we used several triple negative breast cancer cells to identify the molecular mechanisms of adaptation to USMB-induced stress. We found that USMB alters steady-state levels of amino acids, glycolytic intermediates, and citric acid cycle intermediates, suggesting that USMB imposes metabolic stress on cells. USMB treatment acutely reduces ATP levels and stimulates the phosphorylation and activation of AMP-activated protein kinase (AMPK). AMPK is required to restore ATP levels and support cell proliferation post-USMB treatment. These results suggest that AMPK and metabolic perturbations are likely determinants of the antineoplastic efficacy of USMB treatment.
