Metformin Suppresses Pancreatic Tumor Growth With Inhibition of NFκB/STAT3 Inflammatory Signaling

Abstract

Objectives To further elucidate anti-cancer mechanisms of metformin again pancreatic cancer, we evaluated inhibitory effects of metformin on pancreatic tumorigenesis in a genetically-engineered mouse model, and investigated its possible anti-inflammatory and anti-angiogenesis effects. Methods Six-week old LSL-KrasG12D/+;Trp53F2-10 mice (10 per group) were administered once daily intraperitoneally with saline (control) for one week or metformin (125 mg/kg) for one week (Met_1wk) or three weeks (Met_3wk) prior to tumor initiation. All mice continued with their respective injections for six weeks post-tumor initiation. Molecular changes were evaluated by quantitative polymerase chain reaction (PCR), immunohistochemistry, and Western blotting. Results At euthanasia, pancreatic tumor volume in Met_1wk (median, 181.8 mm3) and Met_3wk (median, 137.9 mm3) groups was significantly lower than the control group (median, 481.1 mm3) (P = 0.001 and 0.0009, respectively). No significant difference was observed between Met_1wk and Met_3wk groups (P = 0.51). These results were further confirmed using tumor weight and tumor burden measurements. Furthermore, metformin treatment decreased the phosphorylation of nuclear factor κB (NFκB) and signal transducer and activator of transcription 3 (STAT3) as well as the expression of Sp1 transcription factor and several NFκB-regulated genes. Conclusions Metformin may inhibit pancreatic tumorigenesis by modulating multiple molecular targets in inflammatory pathways.

Metformin use improves the survival of diabetic combined small-cell lung cancer patients

“…The potential mechanisms include the following: (1) alter intracellular signaling pathways. There were two studies identified that metformin inhibited cancer cell growth by activating the AMP-activated protein kinase (AMPK) pathway [16,27], while another study found that metformin suppressed pancreatic tumor growth through inhibiting of NFκB/STAT3 inflammatory signaling pathway [28]. (2) Enhance the tumor cell chemotherapy sensitivity.…”

Metformin Exerts Antiproliferative and Anti-metastatic Effects Against Cholangiocarcinoma Cells by Targeting STAT3 and NF-ĸB

“…Apart from AMPK, metformin exerts anticancer effects via multiple pathways, e.g. inhibition of the mTOR pathway in CCA (19), a decrease of forkhead box protein M1 (FOXM1) in leukemia (23), suppression of STAT3 activation in lung adenocarcinoma (24)and in triple-negative breast cancer (25), and inactivation of STAT3 and NF-ĸB in several cancer cell lines (26,27).…”

(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial

“…Moreover, metformin, by accumulating in neoplastic tissue, may directly affect cancer cells primarily by decreasing insulin/IGF signaling (8,11), disrupting mitochondrial respiration (12), and inhibiting the mTOR pathway by AMP-activated protein kinase (AMPK)-dependent (8,13,14) and -independent mechanisms (15)(16)(17)(18). In addition, other potential direct antitumorigenic effects of metformin include the ability to downregulate specific transcription factors and associated genes (15,19,20), alter microRNAs (5,21), decrease cancer stem cell proliferation (22,23), and reduce DNA damage and inflammation (24). Pharmacoepidemiologic studies have suggested that metformin use is associated with reduced pancreatic cancer risk (25)(26)(27)(28)(29) and an improved cancer prognosis or survival (30,31).…”