A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1 alpha-mediated aerobic glycolysis
Journal
MOLECULAR ONCOLOGY
Journal Volume
Online Version of Record before inclusion in an issue
Date Issued
2022-03-17
Author(s)
Hsing-I Tseng
Yi-Siang Zeng
Jui-Wen Huang
Chih-Lung Lin
Meng-Hsuan Lee
Fan-Wei Yang
Te-Ping Fang
Ai-Chung Mar
Jung-Chen Su
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 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.
Subjects
AMPK
hepatocellular carcinoma
HIF1 alpha
SCT-1015
SDGs
Publisher
WILEY
Type
journal article