Figure 2.

Mechanisms of the Anticancer Effects of SGLT2i

SGLT2 inhibitors (SGLT2i) inhibit glucose uptake by inhibiting SGLTs (SGLT-1 and SGLT-2) and glucose transporters (GLUTs). SGLT2 inhibitors, especially canagliflozin, inhibit mitochondrial complex I–supported cellular respiration, reducing adenosine triphosphate production and activating AMPK. Activated AMPK inhibits acetyl–coenzyme A carboxylase (ACC), suppressing fatty acid synthesis. It also down-regulates forkhead box A1 (FOXA1) and sonic hedgehog signaling molecule (Shh) and inhibits mTOR and p70S6K, thereby suppressing protein synthesis. Inhibited mTOR results in the down-regulation of hypoxia-inducible factor-1α (HIF-1α). SGLT2 inhibitors inhibit the phosphoinositide 3-kinase (PI3K)/AKT pathway. SGLT2 inhibitors inhibit the Hippo signaling pathway by down-regulating the heterogeneous nuclear ribonucleoprotein K (hnRNPK)/YES-associated protein 1 (YAP1) axis. Additionally, SGLT2 inhibitors inhibit epidermal growth factor receptor (EGFR) kinase and angiogenesis activators. Created using BioRender.com. ANG = angiogenin; FA = fatty acid; IL8 = interleukin 8; TIMP1 = tissue inhibitor of metalloproteinase 1; other abbreviations as in Figure 1.