| Autor: |
Tseng, Hsing-I., Yi-Siang Zeng, Ying-Chung Jimmy Lin, Jui-Wen Huang, Chih-Lung Lin, Meng-Hsuan Lee, Fan-Wei Yang, Te-Ping Fang, Ai-Chung Mar, Jung-Chen Su |
| Zdroj: |
Molecular Oncology; Jun2022, Vol. 16 Issue 11, p2274-2294, 21p |
| Abstrakt: |
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 a and ßsubunit 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 (HIF1α) and that SCT-1015-activated AMPK promoted hydroxylation of HIF1αK (402P and 564P), resulting in HIF1a degradation by the ubiquitin-proteasome system. With declined HIF1 a 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
Plný text