The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration

Abstract

ObjectiveThe sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 inhibitors may inhibit the growth of some cancer cells but the mechanism(s) remain unclear.MethodsCellular proliferation and clonogenic survival were used to assess the sensitivity of prostate and lung cancer cell growth to the SGLT2 inhibitors. Oxygen consumption, extracellular acidification rate, cellular ATP, glucose uptake, lipogenesis, and phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase, and the p70S6 kinase were assessed. Overexpression of a protein that maintains complex-I supported mitochondrial respiration (NDI1) was used to establish the importance of this pathway for mediating the anti-proliferative effects of Canagliflozin.ResultsClinically achievable concentrations of Canagliflozin, but not Dapagliflozin, inhibit cellular proliferation and clonogenic survival of prostate and lung cancer cells alone and in combination with ionizing radiation and the chemotherapy Docetaxel. Canagliflozin reduced glucose uptake, mitochondrial complex-I supported respiration, ATP, and lipogenesis while increasing the activating phosphorylation of AMPK. The overexpression of NDI1 blocked the anti-proliferative effects of Canagliflozin indicating reductions in mitochondrial respiration are critical for anti-proliferative actions.ConclusionThese data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations.

Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake

“…Therefore, we consider the suppression of AKT phosphorylation to be highly relevant to canagliflozin‐mediated apoptosis in liver cancer cells. A recent report discussed different mechanism by which canagliflozin could inhibit prostate and lung cancer cell growth independently of glucose uptake and AKT dephosphorylation via AMPK activation and mitochondrial respiration inhibition . However, our current results showed no significant effect of canagliflozin on AMPK activation (data not shown).…”

“…Accordingly, SGLT2‐Is, which target this process, offer unique benefits as blood glucose‐lowering agents and are currently under development as adjuncts to standard care for patients with T2DM. Although normally, SGLT2 is predominantly localized in the kidney, recent studies have revealed SGLT2 expression in certain types of cancer cells; furthermore, inhibition of this transporter can suppress cancer growth . Regarding liver cancers, in our study we observed SGLT2 upregulation in human liver cancer cells relative to PHH and hepatic stellate cells, and found that canagliflozin‐mediated SGLT2 inhibition suppressed intracellular glucose uptake in a dose‐dependent manner.…”

“…Although normally, SGLT2 is predominantly localized in the kidney, recent studies have revealed SGLT2 expression in certain types of cancer cells; furthermore, inhibition of this transporter can suppress cancer growth. 15,34 Regarding liver cancers, in our study we observed SGLT2 upregulation in human liver cancer cells relative to PHH and hepatic stellate cells, and found that canagliflozin-mediated SGLT2 inhibition suppressed intracellular glucose uptake in a dose-dependent manner. These findings indicate that in liver cancer cells, glucose uptake is potentially shared by SGLT2 and GLUT1.…”

AMPK β1 reduces tumor progression and improves survival in p53 null mice

“…Increases in fatty acid synthesis are required to sustain rapid proliferation in many types of cancer [for review, see (Hanahan and Weinberg, 2011; Hirschey et al ., 2015)] including prostate and non‐small‐cell lung cancer (NSCLC) (Shah et al ., 2016; Svensson et al ., 2016; Villani et al ., 2016). Rates of fatty acid synthesis are governed by the expression of ATP‐citrate lyase (ACLY), acetyl‐CoA carboxylase (ACC), and fatty acid synthase (FAS) (Hanahan and Weinberg, 2011; Hirschey et al ., 2015; Shah et al ., 2016; Svensson et al ., 2016; Villani et al ., 2016).…”

“…Rates of fatty acid synthesis are governed by the expression of ATP‐citrate lyase (ACLY), acetyl‐CoA carboxylase (ACC), and fatty acid synthase (FAS) (Hanahan and Weinberg, 2011; Hirschey et al ., 2015; Shah et al ., 2016; Svensson et al ., 2016; Villani et al ., 2016). While AMPK may regulate multiple branches of the lipogenic pathway, direct phosphorylation of ACC has been shown to result in the inhibition of ACC activity, thereby preventing the conversion of acetyl‐CoA to malonyl‐CoA and blocking the entire lipogenic program (Fullerton et al ., 2013; Munday et al ., 1988).…”