期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 25, 期 6, 页码 2806-2815出版社
WILEY
DOI: 10.1111/jcmm.16308
关键词
AMPK; Smad3; TGF‐ β 1
资金
- National Natural Science Foundation of China [81272926, 82060450, 3166033281460374, 31460304]
- Nature Science Foundation of Jiangxi Province [20202BABL206031]
This study demonstrates that AMPK can inhibit the production of TGF-beta 1 through suppressing Smad3 phosphorylation and activation. Metformin can reduce the expression of TGF-beta 1, affecting the growth and survival of gastric cancer cells.
We have previously shown that adenine monophosphate-activated protein kinase (AMPK) regulates transforming growth factor beta (TGF-beta)-triggered Smad3 phosphorylation. Here we report that AMPK inhibits TGF-beta 1 production. First, metformin reduced mRNA levels of TGF-beta 1 in gastric cancer cells, in parallel to the decrease of its protein abundance. The effects were more prominent in the cells containing LKB1, an upstream kinase of AMPK. Second, knockdown of Smad3 by siRNA abrogated the expression of TGF-beta 1. Third, metformin suppressed firefly luciferase activity whose transcription was driven by TGF-beta 1 promoter. In accordance, deletion of the putative binding site of Smad3 in the TGF-beta 1 promoter region severely impaired the promoter activity and response to metformin. Fourth, in support of our in vitro study, clinical treatment of type 2 diabetes with metformin significantly reduced the plasma level of TGF-beta 1. Finally, immunohistochemical studies revealed that TGF-beta 1 was highly expressed in human gastric cancer tissues as compared with adjacent normal tissues. In contrast, p-AMPK exhibited opposite changes. Furthermore, the survival rate of gastric cancer patients was positively correlated with p-AMPK and negative with TGF-beta 1. Therefore, our present studies depict a mechanism underlying AMPK suppression of TGF-beta 1 autoinduction, which is mediated through inhibition of Smad3 phosphorylation and activation. Collectively, our study sheds a light on the potential usage of AMPK activators in the treatment of TGF-beta 1-mediated gastric cancer progression.
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