A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α‐mediated aerobic glycolysis

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.

Crithmum maritimum restores the lipid and metabolic profiles of liver cancer cells to a normal phenotype

“…All the other genes are downregulated [28]. In particular, the activation of AMPK, SIRT1 and SIRT3 has been suggested as a preventative and therapeutic opportunity for HCC [29][30][31]. The data reported in Fig.…”

Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment

“…Heterogeneity of TME is associated with glucose metabolism. It was shown that hypoxic conditions in TME promoted HIF-1-induced glycolysis [204]. HIF-1 promotes glycolysis by upregulating hexokinase and glucose transporters, while inhibiting mitochondrial biosynthesis [204].…”

“…It was shown that hypoxic conditions in TME promoted HIF-1-induced glycolysis [204]. HIF-1 promotes glycolysis by upregulating hexokinase and glucose transporters, while inhibiting mitochondrial biosynthesis [204]. HIF-1 stimulates pyruvate kinase 2 (PKM2) into the nucleus to drive transcription of glycolysis-related genes [205].…”

Metabolism as a New Avenue for Hepatocellular Carcinoma Therapy

“…In fact, some AMPK activators are now being considered as possible drugs for the treatment of metabolic disorders and cancer [ 138 ]. In HCC, a recent report suggested that AMPK activation shows therapeutic potential [ 139 ]. Still, caution is suggested since contrasting results have been reported for cancer therapy [ 140 ].…”