Back to Search
Start Over
A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α-mediated aerobic glycolysis.
- Source :
-
Molecular oncology [Mol Oncol] 2022 Jun; Vol. 16 (11), pp. 2274-2294. Date of Electronic Publication: 2022 Apr 12. - Publication Year :
- 2022
-
Abstract
- 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 α and β-subunit interface, thereby exposing the kinase α 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 HIF1α (402P and 564P), resulting in HIF1α degradation by the ubiquitin-proteasome system. With declined HIF1α 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.<br /> (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Subjects :
- Cell Line, Tumor
Enzyme Activation
Humans
Signal Transduction
AMP-Activated Protein Kinases metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular enzymology
Glycolysis drug effects
Liver Neoplasms drug therapy
Liver Neoplasms enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0261
- Volume :
- 16
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular oncology
- Publication Type :
- Academic Journal
- Accession number :
- 35298869
- Full Text :
- https://doi.org/10.1002/1878-0261.13211