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

Abstract

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.

SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells

“…Likewise, the results of this study provided the first evidence that iSGLT2 treatment triggered S-phase cell cycle arrest and caspase-3-dependent apoptotic cell death in HCT 116 and HT-29 cells. In line with recent reports, SGLT2 inhibition suppressed glucose uptake, lactate release, ATP production and increased AMPK activation, opposing signaling pathways which contribute to metabolic reprogramming and tumor progression [ 34 , 35 , 63 ]. AMPK is generally phosphorylated to decrease energy consumption and restore energetic metabolism when ATP synthesis is impaired or its consumption is accelerated [ 64 ].…”

“…Treatment with iSGLT2 opposed glucose uptake and cisplatin resistance in hepatoblastoma cells [ 6 ], triggered apoptosis and abrogated breast cancer stemness via miR-128-3p overexpression [ 53 , 54 ]. Canagliflozin re-sensitized hepatocellular carcinoma to cisplatin by inducing ferroptosis [ 55 ], regulated glycolysis and glutamine metabolism, inhibited proliferation and clonogenic survival and enhanced radiotherapy efficacy by suppressing mitochondrial oxidative phosphorylation in non-small cell lung cancer [ 35 ]. In CRC patients, treatment with iSGLT2 counteracted cell growth, development and adhesion, and displayed synergic interaction with cetuximab [ 33 , 56 – 59 ].…”

The Cardioprotective and Anticancer Effects of SGLT2 Inhibitors

“…The mechanisms involved with the anticancer effects of SGLT2 inhibitors are depicted in Figure 2 . The activation of AMPK was the most frequently reported mechanism underlying the anticancer properties of SGLT2 inhibitors, 24 , 25 , 129 , 132 , 140 , 142 , 143 , 145 , 148 particularly with canagliflozin. Mechanistically, canagliflozin inhibited mitochondrial complex I–supported cellular respiration and oxidative phosphorylation, leading to reduced adenosine triphosphate production and an elevated adenosine monophosphate/adenosine triphosphate ratio, which in turn induced AMPK phosphorylation and activation.…”

“… 152 In a recent study, canagliflozin not only inhibited the proliferation and clonogenic survival of NSCLC in vitro and in vivo but also enhanced the effectiveness of radiotherapy to mediate these effects. 148 Canagliflozin down-regulated hypoxia-inducible factor-1α protein levels and genes regulating its stability. Down-regulated hypoxia-inducible factor-1α has been attributed to the activation of AMPK and inhibition of mTOR, which serve as critical activators of hypoxia-inducible factor-1α signaling.…”

Editorial: Epigenetic regulation of autophagy in inflammatory diseases

“…Studies on drug regulation of autophagy and epigenetics offer new treatment targets for ID. Canagliflozin, a sodium-glucose cotransporter-2 inhibitor approved by the Food and Drug Administration for the treatment of diabetes, targeted the epigenetic modifiers histone deacetylases 6 and 2, inhibiting the progression of tumors ( 6 , 7 ) and activated autophagy yielding anti-inflammatory effects ( 8 ). Canagliflozin attenuated renal fibrosis in vitro and in vivo through an autophagy-mediated m 6 A modification ( Yang et al.…”