Cell Metabolomics Reveals Berberine-Inhibited Pancreatic Cancer Cell Viability and Metastasis by Regulating Citrate Metabolism

Abstract

Pancreatic cancer (PC) is becoming one of the deadliest cancers, with mortality among the highest worldwide because of its pathogenic latency and the lack of efficient drugs in the clinic. Considering that cancer cells undergo proliferation and differentiation at substantial metabolic costs, as indicated by dysregulated glycolysis and an abnormal TCA cycle induced by mitochondrial damage, we investigated the therapeutic capacity of berberine (BBR) in pancreatic cancer using a cell metabolomics method. A phenotypic assay revealed the significant inhibitory role of BBR in PC cell viability and metastasis. In addition, a precisiontargeted metabolome assay showed that BBR profoundly dysregulated the energy metabolism of PC cells, and phenotypic observations based on imaging indicated that PC cell mitochondria were markedly damaged after BBR treatment. Notably, citrate metabolism and transportation in cell mitochondria were significantly influenced by BBR, which led to the blocked biosynthesis of the defined fatty acids (FAs) through the regulation of ACLY, ACO1, and SLC25A1. Therefore, the regulatory effects of FAs on PC cell proliferation and metastasis may be regulated by BBR through targeting citrate metabolism. Collectively, our in vitro data preliminarily reveals the therapeutic potential of BBR against pancreatic cancer by targeting citrate metabolism, citrate might be a new target for drug development and the treatment against PC, but further experimental verification will be required subsequently. Moreover, our study demonstrated that the cell metabolomics method pertains to the capacity to rapidly explore biochemical functions of natural products.

Berberine as a Potential Anticancer Agent: A Comprehensive Review

“…Based on a phenotypic assay, berberine showed a notable inhibitory role in pancreatic cancer cell metastasis and viability. Additionally, berberine treatment significantly damaged the mitochondria of pancreatic cancer cells and therefore dysregulated their energy metabolism processes [ 72 ]. In pancreatic cancer cells, BBR treatment also influenced citrate metabolism resulting in blocking of the fatty acid biosynthesis.…”

Integrating Network Pharmacology and Experimental Verification to Explore the Mechanism of Effect of Zuojin Pills in Pancreatic Cancer Treatment

“…40 Berberine is also an important component of ZJP, and recent cell metabolomics studies have revealed that berberine decreases pancreatic cancer cell viability and inhibits metastasis by regulating citric acid metabolism. 41 Furthermore, liposomes delivering both berberine and irinotecan were more effective and exhibited lower intestinal toxicity in the treatment of pancreatic cancer than liposomes delivering either component alone. 42 All of the above studies support our network pharmacological prediction and prove the feasibility of network pharmacological methods in the study of the mechanism of action of TCM.…”

Anticancer Potential of Natural Isoquinoline Alkaloid Berberine

“…113,114,118 Berberine is also able to trigger the extrinsic pathway of apoptosis stimulated by TRAIL, FADD, FASL and TNFα that activates caspases 8/7/3 and PARP. 155 Berberine stimulates necrosis by elevating the release of Cyp-D from mitochondria and promoting the translocation of p53 into mitochondria (Fig. 2).…”

“…Berberine treatment also increased amino acids, nucleotides metabolism and glycolysis, but reduced citric acid cycle metabolites and damaged the mitochondria (Table 1). 155…”