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Series GSE239495 Query DataSets for GSE239495
Status Public on Aug 17, 2023
Title Canagliflozin mediates tumor suppression alone and in combination with radiotherapy in non-small cell lung cancer (NSCLC) through inhibition of HIF-1a
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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 anti-proliferative capacity than specific mitochondrial complex-I inhibitors. The treament downregulated genes mediating hypoxia-inducible factor (HIF)-1a stability, metabolism and survival, activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR, a critical activator of HIF-1a signaling. HIF-1a knockdown and stabilization experiments suggested that canagliflozin mediates anti-proliferative effects, in part, through suppression of HIF-1a. 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-1a levels and enhanced the anti-proliferative 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.
Overall design Total RNA was isolated from 3 replicates of A549 cells treated with either 10 uM canagliflozin, 5 Gy radiotherapy (RT) or vehicle (DMSO) for 24h. A total of 9 samples were analyzed.
Contributor(s) Biziotis O, Tsakiridis EE, Ali A, Ahmadi E, Wu J, Wang S, Mekhaeil B, Singh K, Menjolian G, Farrell T, Abdulkarim B, Sur RK, Mesci A, Ellis P, Berg T, Bramson JL, Muti P, Steinberg GR, Tsakiridis T
Citation(s) 37584455
Submission date Jul 28, 2023
Last update date Aug 17, 2023
Contact name Theodoros Tsakiridis
Organization name McMaster University
Street address 699 Concession St
City Hamilton
ZIP/Postal code L8V 5C2
Country Canada
Platforms (1)
GPL18460 Illumina HiSeq 1500 (Homo sapiens)
Samples (9)
GSM7666301 A549 cells, vehicle control, rep1
GSM7666302 A549 cells, vehicle control, rep2
GSM7666303 A549 cells, vehicle control, rep3
BioProject PRJNA999509

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Supplementary file Size Download File type/resource
GSE239495_Annotated_rlog_Normalized_DESeq2_Control_vs_CANA.xlsx 4.5 Mb (ftp)(http) XLSX
GSE239495_Annotated_rlog_Normalized_DESeq2_Control_vs_RT.xls.gz 6.8 Mb (ftp)(http) XLS
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