Liraglutide activates nature killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma

Abstract

Inflammatory IL-6/STAT3 signaling is constitutively activated in diverse cancers and is associated with malignant cell proliferation, invasion and escape of antitumor immunosurveillance. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is commonly used to treat insulin-resistant diabetes. In this study, for the first time, we showed that liraglutide remarkably improved the antitumor immune responses in hepatocellular carcinoma (HCC). Furthermore, we showed that the antitumor activity was mediated by nature killer cells (NKs) but not CD8 + T cells. Finally, we showed that liraglutide enhanced NK-mediated cytotoxicity by suppressing the IL-6/STAT3 signaling pathway in HCC cells. Our findings unveil a novel therapeutic role of liraglutide by manipulating the innate immunity in cancer therapy.

Risk Factors for Hepatocellular Carcinoma in Patients With Non-Alcoholic Fatty Liver Disease

“…The antitumor activity was mediated by nature killer (NK) cells, but not by CD8+ T cells. Furthermore, liraglutide increased NK-mediated cytotoxicity by suppressing the IL-6/STAT3 signaling pathway in HCC cells (65) .…”

“…Associated data on the use of glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrate improvement in NASH and NAFLD. Stud-ies carried out with cell culture and in mice showed that liraglutide suppressed liver carcinogenesis (64,65) . The antitumor activity was mediated by nature killer (NK) cells, but not by CD8+ T cells.…”

Abnormal Metabolism in the Progression of Nonalcoholic Fatty Liver Disease to Hepatocellular Carcinoma: Mechanistic Insights to Chemoprevention

“…GLP-1 receptors may also be expressed on hepatocytes to modulate insulin signaling and lipid metabolism [ 187 ], though this has been debated and liver effects may be indirect [ 188 , 189 ]. However, a number of studies have reported their presence in human hepatocytes and have demonstrated direct effects of GLP-1RAs on hepatocytes and HCC cell lines in vitro [ 187 , 190 , 191 , 192 , 193 , 194 ]. Preclinical animal models have also demonstrated their positive effects on liver lipid metabolism and NAFLD [ 190 , 195 , 196 , 197 ].…”

“…A recent systematic review of 24 completed and 8 ongoing clinical trials found strong evidence for the use of GLP-1RAs in the treatment of NAFLD patients [ 198 ]. Shifting focus to HCC, preclinical animal models demonstrate the antitumorigenic properties of GLP-1RAs [ 194 , 199 ]. The corresponding antitumorigenic effect in vitro using cell culture models support a direct and independent mechanism [ 192 , 193 , 194 ].…”

“…Shifting focus to HCC, preclinical animal models demonstrate the antitumorigenic properties of GLP-1RAs [ 194 , 199 ]. The corresponding antitumorigenic effect in vitro using cell culture models support a direct and independent mechanism [ 192 , 193 , 194 ]. Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that enhance circulating levels of incretins such as GLP-1.…”