Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-κB signaling

Abstract

Accumulating evidence is indicating metformin to possess the potential ability in preventing tumor development and suppressing cancer growth. However, the exact mechanism of its antitumorigenic effects is still not clear. We found that metformin suppressed the ability of cancer to skew macrophage toward M2 phenotype. Metformin treated cancer cells increased macrophage expression of M1-related cytokines IL-12 and TNF-α and attenuated M2-related cytokines IL-8, IL-10, and TGF-β expression. Furthermore, metformin treated cancer cells displayed inhibited secretion of IL-4, IL-10 and IL-13; cytokines important for inducing M2 macrophages. Conversely, M1 inducing cytokine IFN-γ was upper-regulated in cancer cells. Additionally, through increasing AMPK and p65 phosphorylation, metformin treatment activated AMPK-NF-κB signaling of cancer cells that participate in regulating M1 and M2 inducing cytokines expression. Moreover, Compound C, an AMPK inhibitor, significantly increased IL-4, IL-10, and IL-13 expression while BAY-117082, an NF-κB inhibitor, decreased expression. In metformin-treated tumor tissue, the percentage of M2-like macrophages decreased while M1-like macrophages increased. These findings suggest that metformin activates cancer AMPK-NF-κB signaling, a pathway involved in regulating M1/M2 expression and inducing genes for macrophage polarization to anti-tumor phenotype.

Phenotypic functional activities of monocyte change during crosstalk with breast cancer cell and enhancing effect of metformin of IFN-γ-associated antitumor cytokine production

“…The current study provides evidence that MOs cultured with breast cancer cells exhibited high levels of iNOS, but remain without marked change when treated with MET. Our observations are in agreement with earlier findings demonstrating that MET induces antitumoral activity of macrophages during breast cancer (49) and suppresses polarization toward pro-tumoral phenotypes (50). Although arginase activity was downregulated in untreated co-cultured cells, it was upregulated after MET treatment.…”

Metformin as Potential Therapy for High-Grade Glioma

“…Chiang et al, demonstrated the ability of this drug to inhibit the change of the TAMs phenotype to anti-inflammatory. This was done by the effect of metformin on the increase in AMPK activity and the regulation of the AMPK-NF-κB axis [139]. Similar conclusions were made by Wang et al, who additionally emphasized the anti-angiogenic effects of the drug by inhibiting VEGF expression [141].…”

“…In the case of malignant tumors such as GBM, TAMs adopt anti-inflammatory phenotype resulting in the production of anti-tumor immune response inhibiting cytokines, promoting tumor growth and angiogenesis [135][136][137][138]. This is associated with an unfavorable prognosis, which has been demonstrated, among others, in the case of glioma as well as prostate, bladder, breast, and lung cancers [139,140]. Recently, some researchers have suggested the potential effect of metformin in regulating polarization of TAMs reflecting their phenotype.…”

Administration of metformin to increase the efficacy of chemotherapy regimen in cancers; a new look to an old drug

“…Various conditions can stimulate AMPK in the body, such as calorie restriction, which depresses cellular energy supplies and triggers AMPK. This is the reason that calorie constraint has been detected to diminish malignancy occurrence and augment cancer cell death in animal models (15)(16)(17)(18).…”