Metformin activates the STING/IRF3/IFN-β pathway by inhibiting AKT phosphorylation in pancreatic cancer

Dianyun Ren; Gengdu Qin; Jingyuan Zhao; Yan Sun; Bin Zhang; Dan Li; Bo Wang; Xin Jin; Heshui Wu

Metformin activates the STING/IRF3/IFN-β pathway by inhibiting AKT phosphorylation in pancreatic cancer

Am J Cancer Res. 2020 Sep 1;10(9):2851-2864. eCollection 2020.

Authors

Dianyun Ren^{1

2}, Gengdu Qin^{1

2}, Jingyuan Zhao^{1

2}, Yan Sun^{1

2}, Bin Zhang³, Dan Li⁴, Bo Wang^{1

2}, Xin Jin^{2

3}, Heshui Wu^{1

2}

Affiliations

¹ Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430022, China.
² Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430022, China.
³ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430022, China.
⁴ Cardiovascular Medicine Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430022, China.

PMID: 33042621
PMCID: PMC7539786

Abstract

The anti-diabetes drug metformin has emerged as a promising antitumor agent in pancreatic ductal adenocarcinoma (PDAC) among other cancers by promoting the infiltration of immune cells in the tumor microenvironment (TME). However, the mechanisms underlying the antitumor effects of metformin in PDAC remain unclear. In this study, we revealed that metformin induced stimulator of interferon genes (STING) expression in pancreatic cancer cells in a dose- and time-dependent manner. Metformin also activated the STING/IRF3/IFN-β pathway by inhibiting AKT signaling in PDAC cells. Importantly, the combination of metformin with the STING agonist 2'3'-cGAMP exerted synergistic effects in activating the STING/IRF3/IFN-β pathway in pancreatic cancer cells. Additionally, metformin augmented the antitumor effects of 2'3'-cGAMP in mouse models by enhancing the infiltration of T cells in the TME. These findings unveiled a previously unknown mechanism contributing to the antitumor effects of metformin in PDAC, and provide a rationale for its use in combination with existing or novel immunotherapies.

Keywords: AKT pathway; Metformin; PDAC; STING.