PMID- 37584455 OWN - NLM STAT- MEDLINE DCOM- 20231103 LR - 20231104 IS - 1878-0261 (Electronic) IS - 1574-7891 (Print) IS - 1574-7891 (Linking) VI - 17 IP - 11 DP - 2023 Nov TI - Canagliflozin mediates tumor suppression alone and in combination with radiotherapy in non-small cell lung cancer (NSCLC) through inhibition of HIF-1alpha. PG - 2235-2256 LID - 10.1002/1878-0261.13508 [doi] AB - 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)-1alpha stability, metabolism and survival, activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR, a critical activator of hypoxia-inducible factor-1alpha (HIF-1alpha) signaling. HIF-1alpha knockdown and stabilization experiments suggested that canagliflozin mediates antiproliferative effects, in part, through suppression of HIF-1alpha. 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-1alpha 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. CI - (c) 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. FAU - Biziotis, Olga-Demetra AU - Biziotis OD AD - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada. AD - Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada. AD - Department of Oncology, McMaster University, Hamilton, Canada. FAU - Tsakiridis, Evangelia Evelyn AU - Tsakiridis EE AD - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada. AD - Department of Medicine, McMaster University, Hamilton, Canada. FAU - Ali, Amr AU - Ali A AUID- ORCID: 0000-0002-1750-0605 AD - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada. AD - Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada. AD - Department of Oncology, McMaster University, Hamilton, Canada. FAU - Ahmadi, Elham AU - Ahmadi E AD - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada. AD - Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada. AD - Department of Oncology, McMaster University, Hamilton, Canada. FAU - Wu, Jianhan AU - Wu J AD - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada. AD - Department of Medicine, McMaster University, Hamilton, Canada. FAU - Wang, Simon AU - Wang S AD - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada. AD - Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada. AD - Department of Oncology, McMaster University, Hamilton, Canada. FAU - Mekhaeil, Bassem AU - Mekhaeil B AD - Department of Oncology, McMaster University, Hamilton, Canada. FAU - Singh, Kanwaldeep AU - Singh K AD - Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada. AD - Department of Oncology, McMaster University, Hamilton, Canada. FAU - Menjolian, Gabe AU - Menjolian G AD - Radiotherapy Program, Juravinski Cancer Centre, Hamilton, Canada. FAU - Farrell, Thomas AU - Farrell T AD - Radiation Physics Program, Juravinski Cancer Centre, Hamilton, Canada. FAU - Abdulkarim, Bassam AU - Abdulkarim B AD - Department of Oncology, McGill University, Montreal, Canada. FAU - Sur, Ranjan K AU - Sur RK AD - Department of Oncology, McMaster University, Hamilton, Canada. AD - Division of Radiation Oncology, Juravinski Cancer Centre, Hamilton, Canada. FAU - Mesci, Aruz AU - Mesci A AD - Department of Oncology, McMaster University, Hamilton, Canada. FAU - Ellis, Peter AU - Ellis P AD - Department of Oncology, McMaster University, Hamilton, Canada. FAU - Berg, Tobias AU - Berg T AD - Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada. AD - Department of Oncology, McMaster University, Hamilton, Canada. FAU - Bramson, Jonathan L AU - Bramson JL AD - Department of Oncology, McMaster University, Hamilton, Canada. AD - Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada. AD - Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Canada. FAU - Muti, Paola AU - Muti P AD - Department of Oncology, McMaster University, Hamilton, Canada. AD - Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy. FAU - Steinberg, Gregory R AU - Steinberg GR AD - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada. AD - Department of Medicine, McMaster University, Hamilton, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada. FAU - Tsakiridis, Theodoros AU - Tsakiridis T AUID- ORCID: 0000-0002-8675-4422 AD - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Canada. AD - Centre for Discovery in Cancer Research, McMaster University, Hamilton, Canada. AD - Department of Oncology, McMaster University, Hamilton, Canada. AD - Division of Radiation Oncology, Juravinski Cancer Centre, Hamilton, Canada. AD - Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada. LA - eng GR - 201709FDN-CEBA-116200/CAPMC/CIHR/Canada GR - 201709FDN-CEBA-116200/CAPMC/CIHR/Canada PT - Journal Article DEP - 20230827 PL - United States TA - Mol Oncol JT - Molecular oncology JID - 101308230 RN - 0SAC974Z85 (Canagliflozin) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 0 (RNA, Small Interfering) SB - IM MH - Humans MH - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/radiotherapy MH - *Lung Neoplasms/drug therapy/genetics/radiotherapy MH - Canagliflozin/pharmacology/therapeutic use MH - Hypoxia-Inducible Factor 1, alpha Subunit/genetics MH - Cell Line, Tumor MH - TOR Serine-Threonine Kinases/metabolism MH - RNA, Small Interfering/genetics PMC - PMC10620129 OTO - NOTNLM OT - HIF-1alpha OT - canagliflozin OT - lung cancer OT - mTOR OT - radiotherapy COIS- The authors declare no conflict of interest. EDAT- 2023/08/16 12:42 MHDA- 2023/11/03 06:43 PMCR- 2023/08/27 CRDT- 2023/08/16 08:43 PHST- 2023/05/26 00:00 [revised] PHST- 2023/02/17 00:00 [received] PHST- 2023/08/14 00:00 [accepted] PHST- 2023/11/03 06:43 [medline] PHST- 2023/08/16 12:42 [pubmed] PHST- 2023/08/16 08:43 [entrez] PHST- 2023/08/27 00:00 [pmc-release] AID - MOL213508 [pii] AID - 10.1002/1878-0261.13508 [doi] PST - ppublish SO - Mol Oncol. 2023 Nov;17(11):2235-2256. doi: 10.1002/1878-0261.13508. Epub 2023 Aug 27.