非小细胞肺癌（Non-small cell lung cancer，NSCLC）的预后不佳，有效的治疗策略缺乏。糖尿病药物坎格列汀（canagliflozin）抑制NSCLC细胞的增殖以及介导细胞生长和存活的哺乳动物雷帕霉素靶蛋白（mTOR）信号通路，但尚不清楚该药物是否能够在与细胞毒疗法联合应用时增强治疗效果。在这里，我们评估了坎格列汀对NSCLC细胞株和异种移植瘤中对细胞毒疗法的响应的影响。我们采用了核糖核酸测序（RNA-seq）、实时定量聚合酶链反应（RT-qPCR）、代谢功能、小干扰核糖核酸（siRNA）沉默和蛋白质表达分析等机制分析方法。我们发现坎格列汀抑制NSCLC细胞的增殖和克隆存活，并增强了放射治疗的疗效以介导这些效应并抑制NSCLC异种移植瘤的生长。坎格列汀单独治疗中度抑制了线粒体氧化磷酸化，并显示出比特异性线粒体复合物I抑制剂更强的抗增殖能力。该治疗降调了介导缺氧诱导因子（HIF）-1α稳定性、代谢和存活的基因，激活了腺苷酸活化蛋白激酶（AMPK），并抑制了mTOR，HIF-1α信号通路的关键激活剂。HIF-1α沉默和稳定实验表明，坎格列汀在一定程度上通过抑制HIF-1α介导了抗增殖作用。转录调控网络分析确定了组蛋白去乙酰化酶2（HDAC2），一种受坎格列汀抑制的基因，作为坎格列汀转录重编程的关键介质。HDAC2沉默消除了HIF-1α水平并增强了坎格列汀的抗增殖作用。被坎格列汀抑制的HDAC2调控的基因与数个临床NSCLC数据集中的预后不良相关。此外，我们还提供了坎格列汀改善NSCLC对化疗的反应的证据。总之，坎格列汀可能是一种与细胞毒疗法联合发展的NSCLC的有希望的治疗方法。本文受版权保护。版权所有。

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)-1α stability, metabolism and survival, activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR, a critical activator of HIF-1α signaling. HIF-1α knockdown and stabilization experiments suggested that canagliflozin mediates anti-proliferative 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 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.This article is protected by copyright. All rights reserved.