https://scholars.lib.ntu.edu.tw/handle/123456789/609352
標題: | A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1 alpha-mediated aerobic glycolysis | 作者: | Hsing-I Tseng Yi-Siang Zeng YING-CHUNG LIN Jui-Wen Huang Chih-Lung Lin Meng-Hsuan Lee Fan-Wei Yang Te-Ping Fang Ai-Chung Mar Jung-Chen Su |
關鍵字: | AMPK;hepatocellular carcinoma;HIF1 alpha;SCT-1015 | 公開日期: | 17-三月-2022 | 出版社: | WILEY | 卷: | Online Version of Record before inclusion in an issue | 來源出版物: | MOLECULAR ONCOLOGY | 摘要: | Hepatocellular carcinoma (HCC) is characterized by rapid growth, early vascular invasion, and high metastasis. Currently available US Food and Drug Administration (FDA)-approved drugs show low therapeutic efficacy, limiting HCC treatment to chemotherapy. We designed and synthesized a novel small molecule, SCT-1015, that allosterically activated adenosine monophosphate-activated protein kinase (AMPK) to suppress the aerobic glycolysis in HCC. SCT-1015 was shown to bind the AMPK alpha and beta-subunit interface, thereby exposing the kinase a domain to the upstream kinases, resulting in the increased AMPK activity. SCT-1015 dramatically reduced HCC cell growth in vitro and tumor growth in vivo. We further found that AMPK formed protein complexes with hypoxia-inducible factor 1-alpha (HIF1 alpha) and that SCT-1015-activated AMPK promoted hydroxylation of HIF1 alpha (402P and 564P), resulting in HIF1 alpha degradation by the ubiquitin-proteasome system. With declined HIF1 alpha abundance, many glycolysis-related enzymes were downregulated, suppressing aerobic glycolysis, and promoting oxidative phosphorylation. These results indicated that SCT-1015 channeled HCC cells into an unfavorable metabolic status. Overall, we reported SCT-1015 as a direct activator of AMPK signaling that held therapeutic potential in HCC. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/609352 | ISSN: | 1574-7891 | DOI: | 10.1002/1878-0261.13211 |
顯示於: | 生命科學系 |
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