The SGLT2 inhibitor canagliflozin suppresses growth and enhances prostate cancer response to radiotherapy.

Autor: Ali A; Departments of Oncology, McMaster University, Hamilton, ON, Canada.; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada., Mekhaeil B; Departments of Oncology, McMaster University, Hamilton, ON, Canada., Biziotis OD; Departments of Oncology, McMaster University, Hamilton, ON, Canada.; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada., Tsakiridis EE; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.; Departments of Medicine, McMaster University, Hamilton, ON, Canada., Ahmadi E; Departments of Oncology, McMaster University, Hamilton, ON, Canada.; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada., Wu J; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.; Departments of Medicine, McMaster University, Hamilton, ON, Canada., Wang S; Departments of Oncology, McMaster University, Hamilton, ON, Canada.; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada., Singh K; Departments of Oncology, McMaster University, Hamilton, ON, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada., Menjolian G; Department of Radiotherapy, Juravinski Cancer Center, Hamilton, ON, Canada., Farrell T; Department of Physics, Juravinski Cancer Center, Hamilton, Ontario, Canada., Mesci A; Departments of Oncology, McMaster University, Hamilton, ON, Canada.; Department of Radiation Oncology, Juravinski Cancer Center, Hamilton, ON, Canada., Liu S; Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada., Berg T; Departments of Oncology, McMaster University, Hamilton, ON, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada., Bramson JL; Departments of Oncology, McMaster University, Hamilton, ON, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada., Steinberg GR; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.; Departments of Medicine, McMaster University, Hamilton, ON, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada., Tsakiridis T; Departments of Oncology, McMaster University, Hamilton, ON, Canada. tsakirt@mcmaster.ca.; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada. tsakirt@mcmaster.ca.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada. tsakirt@mcmaster.ca.; Department of Radiation Oncology, Juravinski Cancer Center, Hamilton, ON, Canada. tsakirt@mcmaster.ca.; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. tsakirt@mcmaster.ca.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Sep 08; Vol. 6 (1), pp. 919. Date of Electronic Publication: 2023 Sep 08.
DOI: 10.1038/s42003-023-05289-w
Abstrakt: Radiotherapy is a non-invasive standard treatment for prostate cancer (PC). However, PC develops radio-resistance, highlighting a need for agents to improve radiotherapy response. Canagliflozin, an inhibitor of sodium-glucose co-transporter-2, is approved for use in diabetes and heart failure, but is also shown to inhibit PC growth. However, whether canagliflozin can improve radiotherapy response in PC remains unknown. Here, we show that well-tolerated doses of canagliflozin suppress proliferation and survival of androgen-sensitive and insensitive human PC cells and tumors and sensitize them to radiotherapy. Canagliflozin blocks mitochondrial respiration, promotes AMPK activity, inhibits the MAPK and mTOR-p70 S6k /4EBP1 pathways, activates cell cycle checkpoints, and inhibits proliferation in part through HIF-1α suppression. Canagliflozin mediates transcriptional reprogramming of several metabolic and survival pathways known to be regulated by ETS and E2F family transcription factors. Genes downregulated by canagliflozin are associated with poor PC prognosis. This study lays the groundwork for clinical investigation of canagliflozin in PC prevention and treatment in combination with radiotherapy.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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