Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-κB signaling.
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.
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Chi-Fu
CF
Chiang
Medical Research Center, Cardinal Tien Hospital, School of Medicine, New Taipei City, Taiwan.
Ting-Ting
TT
Chao
Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Yu-Fu
YF
Su
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Chia-Chen
CC
Hsu
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Chu-Yen
CY
Chien
Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Kuo-Chou
KC
Chiu
National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
Shine-Gwo
SG
Shiah
Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Chien-Hsing
CH
Lee
Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, Tainan, Taiwan.
Shyun-Yeu
SY
Liu
Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.|Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
Yi-Shing
YS
Shieh
D055372:AMP-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D016328:NF-kappa B; D008687:Metformin; D055372:AMP-Activated Protein Kinases
NF-κB; breast cancer; macrophage polarization; metformin; microenvironment