SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia

Ali R Nasiri,Rachel J Perry,Marcos R Rodrigues,Zongyu Li,Brooks P Leitner

doi:10.1186/s40170-019-0203-1

Ali R Nasiri, Rachel J Perry + Show 3 more

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https://doi.org/10.1186/s40170-019-0203-1

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Abstract

BackgroundObesity confers an increased risk and accelerates the progression of multiple tumor types in rodents and humans, including both breast and colon cancer. Because sustained weight loss is rarely achieved, therapeutic approaches to slow or prevent obesity-associated cancer development have been limited, and mechanistic insights as to the obesity-cancer connection have been lacking.MethodsE0771 breast tumors and MC38 colon tumors were treated in vivo in mice and in vitro with two mechanistically different insulin-lowering agents, a controlled-release mitochondrial protonophore (CRMP) and sodium-glucose cotransporter-2 (SGLT2) inhibitors, and tumor growth and glucose metabolism were assessed. Groups were compared by ANOVA with Bonferroni’s multiple comparisons test.ResultsDapagliflozin slows tumor growth in two mouse models (E0771 breast cancer and MC38 colon adenocarcinoma) of obesity-associated cancers in vivo, and a mechanistically different insulin-lowering agent, CRMP, also slowed breast tumor growth through its effect to reverse hyperinsulinemia. In both models and with both agents, tumor glucose uptake and oxidation were not constitutively high, but were hormone-responsive. Restoration of hyperinsulinemia by subcutaneous insulin infusion abrogated the effects of both dapagliflozin and CRMP to slow tumor growth.ConclusionsTaken together, these data demonstrate that hyperinsulinemia per se promotes both breast and colon cancer progression in obese mice, and highlight SGLT2 inhibitors as a clinically available means of slowing obesity-associated tumor growth due to their glucose- and insulin-lowering effects.

Highlights

Obesity confers an increased risk and accelerates the progression of multiple tumor types in rodents and humans, including both breast and colon cancer
We have recently demonstrated that mitochondrial uncoupling with a controlled-release mitochondrial protonophore (CRMP) both prevents and reverses insulin resistance and, as a result, hyperinsulinemia by correcting non-alcoholic fatty liver disease (NAFLD) [34], and that the reversal of hyperinsulinemia slows tumor growth in two mouse models of colon cancer, MC38 tumor-bearing and ApcMin+/- mice [35]
E0771 tumor glucose metabolism was insulin-responsive: glucose uptake and oxidation were increased in tumors of HFD fed, hyperinsulinemic mice but normalized with dapagliflozin treatment; restoring hyperinsulinemia via subcutaneous insulin infusion increased tumor glucose uptake and oxidation to rates observed in HFD control mice

Summary

Introduction

Obesity confers an increased risk and accelerates the progression of multiple tumor types in rodents and humans, including both breast and colon cancer. The ability of insulin to stimulate tumor cell proliferation is likely multifactorial and has been attributed to stimulation of DNA replication and cell cycle progression, potentially by activation of the PI3K/Akt/FOXO1 signaling pathway, increased accumulation of DNA damage, and increases in glucose uptake and/or oxidation Consistent with the latter mechanism, we have recently shown that insulin’s ability to promote glucose uptake and oxidation in vitro constitutes a metabolic signature of obesity-associated tumor types [6], suggesting that insulin-lowering therapies may be an attractive approach to slow obesity-associated tumor growth, thereby prolonging the window during which curative therapies may be possible

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