Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma

Abstract

Summary The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss of function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites acetyl-CoA carboxylase 1 (ACC1 Ser79Ala) and ACC2 (ACC2 Ser212Ala) have increased liver de novo lipogenesis (DNL) and liver lesions. The same mutation in ACC1 also increases DNL and proliferation human liver cancer cells. Consistent with these findings, a novel, liver specific ACC inhibitor (ND-654), that mimics the effects of ACC phosphorylation, inhibits hepatic DNL and the development of HCC, improving survival of tumor-bearing rats when used alone and in combination with the multi-kinase inhibitor sorafenib. These studies highlight the importance of DNL and dysregulation of AMPK-mediated ACC phosphorylation in accelerating HCC and the potential of ACC inhibitors for treatment.

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

“…SIRT1-mediated deacetylation controls the dual function of MRPS5 in regulating the switch of mitochondrial-dependent energy supply to glycolysis in liver CSCs under hypoxia [51]. Attenuated phosphorylation of ACC1 by AMPK improved tumor survival under sorafenib treatment [75]. These findings confirm that post-translational modification is an important pathway for regulating tumor adaptation to sorafenib during metabolic reprogramming.…”

“…Inhibiting fatty acid synthase (FASN) blocked lipid synthesis and restored the anti-tumor effect of sorafenib [74]. Mutation of two AMPK phosphorylation sites within ACC1 enhanced de novo lipogenesis (DNL), and inhibition of ACC1 improved sorafenib efficacy in a rat model [75]. One study revealed upregulated SCD1 in sorafenib-resistant HCC cell lines, and its expression predicted clinical benefit for sorafenib in patients.…”

AMP-activated protein kinase: the current landscape for drug development

“…Recent studies testing an AMPK activator (PF-06409577) that has greater selectivity towards β1-containing complexes but also activates β2-containing complexes has shown positive effects on NAFLD and NASH in non-human primates, effects that were also observed in mice and shown to be completely dependent on liver AMPK and the phosphorylation of ACC 25 . Furthermore, novel small molecule inhibitors of ACC, which mimic the effects of AMPK phosphorylation, are currently in clinical development for the treatment of NASH 214 , non-small-cell lung carcinoma 215 and hepatocellular carcinoma 216 . Interestingly, this activation of liver AMPK promoted a dramatic increase in SREBP1C, consistent with previous observations obtained with small molecule inhibitors of ACC 217 .…”

M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma

“…Mounting evidence indicates that abnormal lipid metabolism plays crucial parts in HCC development [22][23][24], and HDGF was recently reported to be a lipogenesis-associated gene in tumorigenesis [25]. We started to explore whether LINC00958 could affect lipogenesis in HCC cells.…”