Research Papers:

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

Chi-Fu Chiang, Ting-Ting Chao, Yu-Fu Su, Chia-Chen Hsu, Chu-Yen Chien, Kuo-Chou Chiu, Shine-Gwo Shiah, Chien-Hsing Lee, Shyun-Yeu Liu and Yi-Shing Shieh _

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Oncotarget. 2017; 8:20706-20718. https://doi.org/10.18632/oncotarget.14982

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Chi-Fu Chiang1, Ting-Ting Chao2, Yu-Fu Su3, Chia-Chen Hsu1, Chu-Yen Chien1, Kuo-Chou Chiu4, Shine-Gwo Shiah5, Chien-Hsing Lee6, Shyun-Yeu Liu7, Yi-Shing Shieh4,8

1Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan

2Medical Research Center, Cardinal Tien Hospital, School of Medicine, New Taipei City, Taiwan

3Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

4Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

5National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan

6Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

7Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, Tainan, Taiwan

8Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan

Correspondence to:

Yi-Shing Shieh, email: [email protected]

Chien-Hsing Lee, email: [email protected]

Shyun-Yeu Liu, email: [email protected]

Keywords: breast cancer, macrophage polarization, metformin, microenvironment, NF-κB

Received: December 15, 2016     Accepted: January 24, 2017     Published: February 01, 2017


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.

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