Identification of Pyruvate Carboxylase as the Cellular Target of Natural Bibenzyls with Potent Anticancer Activity against Hepatocellular Carcinoma via Metabolic Reprogramming

Abstract

Cancer cell proliferation in some organs often depends on conversion of pyruvate to oxaloacetate via pyruvate carboxylase (PC) for replenishing the tricarboxylic acid cycle to support biomass production. In this study, PC was identified as the cellular target of erianin using the photoaffinity labeling-click chemistry-based probe strategy. Erianin potently inhibited the enzymatic activity of PC, which mediated the anticancer effect of erianin in human hepatocellular carcinoma (HCC). Erianin modulated cancer-related gene expression and induced changes in metabolic intermediates. Moreover, erianin promotes mitochondrial oxidative stress and inhibits glycolysis, leading to insufficient energy required for cell proliferation. Analysis of 14 natural analogs of erianin showed that some compounds exhibited potent inhibitory effects on PC. These results suggest that PC is a cellular target of erianin and reveal the unrecognized function of PC in HCC tumorigenesis; erianin along with its analogs warrants further development as a novel therapeutic strategy for the treatment of HCC.

Bioinformatics analysis and experimental verification of the prognostic and biological significance mediated by fatty acid metabolism related genes for hepatocellular carcinoma

“…When carcinogenic signals are blocked, cancer cells may be able to survive in the adverse microenvironments by metabolic reprogramming (9). Increasing evidence supports the critical involvement of metabolic reprogramming in tumor onset and progression (10)(11)(12). FA metabolism disorder has become a typical cancer cell characteristic (13).…”

CRISPR Cas9-mediated ablation of pyruvate carboxylase gene in colon cancer cell line HT-29 inhibits growth and migration, induces apoptosis and increases sensitivity to 5-fluorouracil and glutaminase inhibitor

“…Recently, two small molecules, namely, ZY-444 ( 50 ) and Erianin ( 51 ) have been reported to inhibit PC activity. They also possess a very low IC 50 within sub-micromolar range and can inhibit growth of many types of cancer including breast, ovarian, lung, colorectal, lung and hepatocellular cancers with minimal effect on normal cells.…”

Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

“…As recently, a natural derivative Erianin was found to be the most potent PC inhibitor and suppress BC cell viability with high potency, thus functioning as an effective tool for illustrating the mechanism of PC in cancer and a potential drug candidate for cancer therapeutic (Figure 15). 324 In addition, despite most of the cancer cells preferring glycolysis over oxidative phosphorylation (OXPHOS) for growth, the metabolic flexibility of several of the deadliest malignancies, especially pancreatic ductal adenocarcinoma (PDAC), depends on OXPHOS to sustain cell survival and metastasis as well as develop resistance to treatment. 325 As a highly expressed protein in lipogenic pancreatic cell lines, MYOF has negative correlation with glycolytic activity (Figure 13).…”

“…As recently, a natural derivative Erianin was found to be the most potent PC inhibitor and suppress BC cell viability with high potency, thus functioning as an effective tool for illustrating the mechanism of PC in cancer and a potential drug candidate for cancer therapeutic (Figure 15). 324 …”