Journal
ONCOTARGET
Volume 6, Issue 34, Pages 36441-36455Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5541
Keywords
metformin; macrophage polarization; cancer metastasis; AMPK alpha 1
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Funding
- National Natural Science Foundation of China [91029745, 81473226]
- Zhejiang Provincial Construction Foundation of China [WKJ-ZJ-10]
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Accumulated evidence suggests that M2-like polarized tumor associated macrophages (TAMs) plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-like TAMs as an appealing target for therapy intervention. Here we found that metformin significantly suppressed IL-13 induced M2-like polarization of macrophages, as illustrated by reduced expression of CD206, down-regulation of M2 marker mRNAs, and inhibition of M2-like macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPK alpha 1 activation in macrophage and silencing of AMPKa1 partially abrogated the inhibitory effect of metformin in IL-13 induced M2-like polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-like polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-like macrophage was decreased and the area of pericyte-coated vessels was increased. Further, the anti-metastatic effect of metformin was abolished when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-like polarization of macrophages partially through AMPKa1, which plays an important role in metformin inhibited metastasis of Lewis lung cancer.
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