Canagliflozin mediates tumor suppression alone and in combination with radiotherapy in non-small cell lung cancer (NSCLC) through inhibition of HIF-1α.

Autor:	Biziotis OD; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada.; Department of Oncology, McMaster University, Hamilton, Canada., Tsakiridis EE; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada.; Department of Medicine, McMaster University, Hamilton, Canada., Ali A; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada.; Department of Oncology, McMaster University, Hamilton, Canada., Ahmadi E; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada.; Department of Oncology, McMaster University, Hamilton, Canada., Wu J; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada.; Department of Medicine, McMaster University, Hamilton, Canada., Wang S; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada.; Department of Oncology, McMaster University, Hamilton, Canada., Mekhaeil B; Department of Oncology, McMaster University, Hamilton, Canada., Singh K; Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada.; Department of Oncology, McMaster University, Hamilton, Canada., Menjolian G; Radiotherapy Program, Juravinski Cancer Centre, Hamilton, Canada., Farrell T; Radiation Physics Program, Juravinski Cancer Centre, Hamilton, Canada., Abdulkarim B; Department of Oncology, McGill University, Montréal, Canada., Sur RK; Department of Oncology, McMaster University, Hamilton, Canada.; Division of Radiation Oncology, Juravinski Cancer Centre, Hamilton, Canada., Mesci A; Department of Oncology, McMaster University, Hamilton, Canada., Ellis P; Department of Oncology, McMaster University, Hamilton, Canada., Berg T; Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada.; Department of Oncology, McMaster University, Hamilton, Canada., Bramson JL; Department of Oncology, McMaster University, Hamilton, Canada.; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.; Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Canada., Muti P; Department of Oncology, McMaster University, Hamilton, Canada.; Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy., Steinberg GR; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada.; Department of Medicine, McMaster University, Hamilton, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada., Tsakiridis T; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada.; Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada.; Department of Oncology, McMaster University, Hamilton, Canada.; Division of Radiation Oncology, Juravinski Cancer Centre, Hamilton, Canada.; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.
Jazyk:	angličtina
Zdroj:	Molecular oncology [Mol Oncol] 2023 Nov; Vol. 17 (11), pp. 2235-2256. Date of Electronic Publication: 2023 Aug 27.
DOI:	10.1002/1878-0261.13508
Abstrakt:	Non-small cell lung cancer (NSCLC) has a poor prognosis, and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA-seq), real-time quantitative PCR (RT-qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown, and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater antiproliferative capacity than specific mitochondrial complex-I inhibitors. The treatment downregulated genes mediating hypoxia-inducible factor (HIF)-1α stability, metabolism and survival, activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR, a critical activator of hypoxia-inducible factor-1α (HIF-1α) signaling. HIF-1α knockdown and stabilization experiments suggested that canagliflozin mediates antiproliferative effects, in part, through suppression of HIF-1α. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin's transcriptional reprogramming. HDAC2 knockdown eliminated HIF-1α levels and enhanced the antiproliferative effects of canagliflozin. HDAC2-regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC. (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze:	MEDLINE
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