Antitumor effects of metformin are a result of inhibiting nuclear factor kappa B nuclear translocation in esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer that has proven difficult to treat despite multidisciplinary therapy, and a new treatment strategy is demanded. Metformin is used for type 2 diabetes mellitus and its antitumor effects have been reported recently. Metformin exerts antitumor effects in various respects, such as inhibiting inflammation, tumor growth and epithelial‐mesenchymal transition (EMT). However, few reports have described the efficacy of metformin on ESCC, and their findings have been controversial. We analyzed the antitumor effects of metformin and clarified its effects on anti‐inflammation, growth suppression and EMT inhibition. Activation of nuclear factor kappa B (NF‐κB), the major transcription factor induced by inflammation, was investigated by immunostaining. We found that localization of NF‐κB in the nucleus was reduced after metformin treatment. This suggests that metformin inhibited the activation of NF‐κB. Metformin inhibited tumor growth and induced apoptosis in ESCC cell lines. Associated with EMT, we examined cell motility by a wound healing assay and the epithelial marker E‐cadherin expression of various ESCC cell lines by western blotting. Metformin inhibited cell motility and induced E‐cadherin expression. In conclusion, metformin showed multiple antitumor effects such as growth suppression, invasion inhibition, and control of EMT by inhibiting NF‐κB localization on ESCC. Further exploration of the marker of treatment efficacy and combination therapy could result in the possibility for novel treatment to use metformin on ESCC.

Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-κB/miR-155-5p inflammatory loop

“…Metformin significantly inhibits the migration of NF-κB from the cytoplasm to the nucleus, thereby inhibiting the subsequent inflammatory cascade[ 19 ]. Sekino et al [ 55 ] performed immunostaining to determine the intracellular localization of NF-κB. In the control group, NF-κB was localized in the cytoplasm and nucleus, while in the metformin-treated group, nuclear NF-κB expression was significantly decreased.…”

“…In the control group, NF-κB was localized in the cytoplasm and nucleus, while in the metformin-treated group, nuclear NF-κB expression was significantly decreased. Thus, metformin affects the level of NF-κB in the nucleus, thereby altering the activation of the NF-κB signalling pathway and further modulating downstream inflammatory pathways[ 55 ]. Therefore, metformin relieves inflammation by inhibiting the expression of NF-κB.…”

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

“…Metformin-mediated activation of AMPK and subsequent modulation and regulation of intracellular proteins and their functions can explain several of the biological functions as well as its anti-cancer/ anti-proliferative effects that was observed in most cancer cells ( Figure 2) [44,45,[90][91][92][93]. Activation of AMPK in cancer cells is associated with inhibition of the mTORC1, c-Myc, and NF-κB pathways and activation of DICER and the p53 pathway, all of which reportedly exert tumor suppressive, anti-proliferative, anti-migratory, and pro-apoptotic effects through various intracellular mediators, activation of anti-oncogenic genes, and downregulation of pro-oncogenic genes [94][95][96][97][98][99][100][101][102][103][104][105]. Metformin treatment-associated AMPK activation leads to the phosphorylation of tuberous sclerosis-2 (TSC2) or raptor and subsequent mTORC1 pathway inhibition, thereby reducing the cellular translational process/protein synthesis and overall cell survival [93,[106][107][108][109][110].…”

Role of p53 Family Proteins in Metformin Anti-Cancer Activities

“…In addition, metformin can suppress the expression of cyclin D1, CDK4 and CDK6, resulting in ESCC cell growth retardation66 (Figure 1B). Furthermore, metformin can inhibit migration and invasion of ESCC cells via inhibiting NF-κB nuclear localization67 or AKT signaling68 (Figure 1B). Moreover, metformin can enhance esophagus cancer cell sensitivity to chemotherapeutic drugs, 5-FU69 or cisplatin70, 71.…”