Acetyl-CoA carboxylase inhibitors attenuate WNT and Hedgehog signaling and suppress pancreatic tumor growth

Abstract

Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo fatty acid synthesis, and its ACC1 isoform is overexpressed in pancreatic and various other cancers. The activity of many oncogenic signaling molecules, including WNT and Hedgehog (HH), is post-translationally modified by lipidation. Here, we report that inhibition of ACC by a small molecule inhibitor, BAY ACC002, blocked WNT3A lipidation, secretion, and signaling. In pancreatic cancer cells, where WNT and HH are key oncogenic drivers, ACC inhibition simultaneously suppressed WNT and HH signaling, and led to anti-proliferative effects. Treatment with ACC inhibitors blocked tumor growth and converted the poorly differentiated histological phenotype to epithelial phenotype in multiple cell line-based and patient-derived pancreatic cancer xenograft models. Together, our data highlight the potential utility of ACC inhibitors for pancreatic cancer treatment, and provide novel insight into the link between upregulated de novo fatty acid synthesis in cancer cells, protein lipidation, and oncogenic signaling.

Acetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems

“… 30 , 31 , 32 , 33 Inhibition of proliferation alone, however, is unlikely to account for the effects of PF-05221034 because inhibition of HSC activation as assessed by collagen staining was observed at lower doses (EC 50 = 5 nmol/L) than those that suppressed HSC proliferation (EC 50 = 35 nmol/L). ACC inhibitors also have been shown to modulate Wnt and Hedgehog signaling in some systems, 34 both of which contribute to HSC activation. 29 Additional studies are needed to determine the precise molecular mechanism underlying the effects of ACC inhibition on HSC activation.…”

The Role of Dysfunctional Adipose Tissue in Pancreatic Cancer: A Molecular Perspective

“…Several molecules have been developed and investigated in pre-clinical and clinical studies. Among FA synthesis inhibitors, BAY ACC022 and SB-204990, respectively targeting the Acetyl-CoA carboxylase (ACC) and ATP citrate lyase (ACLY), reduced tumor growth in pancreatic cancer xenograft models [187,188]. In this context, promising findings in PC pre-clinical studies have been also obtained by blocking different domains of the multi-enzyme complex fatty acid synthase (FASN) with the two agents, epigallocatechin-3 gallate and orlistat [189,190].…”

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

“…Furthermore, oral administration of another ACC inhibitor ND-646 has been described to attenuate tumor growth of lung cancer cells in mice [ 12 ]. For pancreatic cancer, BAY ACC022 has been tested by oral administration: after inoculation of pancreatic cancer cells mice administered with the ACC inhibitor had less tumor volume than controls [ 91 ].…”