Abstract
The occurrence and progress of colon cancer are closely associated with obesity. Therefore, the lipid metabolism, especially fatty acid metabolism, is a significant section of energy homeostasis in colon cancer cells, and it affects many important cellular processes. Oroxylin A is one of the main bioactive flavonoids of Scutellariae radix, which has a strong anticancer effect but low toxicity to normal tissue. In previous studies, we have proved that oroxylin A reprogrammes metabolism of cancer cells by inhibiting glycolysis. Here, we further investigated the metabolism-modulating effects of oroxylin A on the fatty acid metabolism in colon cancer cells under hypoxia. We found that HIF1α upregulated adipophilin, fatty acid synthase and sterol regulatory element-binding protein 1, and downregulated carnitine palmitoyltransferase 1 (CPT1), resulting in the promoted lipid uptake and transport, increased de novo fatty acid synthesis and suppressed fatty acid oxidation. Oroxylin A inactivated HIF1α and reprogrammed fatty acid metabolism of HCT116 cells, decreasing intracellular fatty acid level and enhancing fatty acid oxidation. Furthermore, the rapid decrease of fatty acid level caused by oroxylin A inhibited the nuclear translocation of β-cantenin and inactivated the Wnt pathway, arousing cell cycle arrest in G2/M phase. In vivo studies demonstrated that high-fat diet increased the incidence of colon cancer and accelerated tumor development. Importantly, besides the growth inhibitory effects on colon cancer xenograft, oroxylin A prevented carcinogenesis and delayed progress of primary colon cancer as well. Our studies enriched the metabolic regulatory mechanism of oroxylin A, and suggested that oroxylin A was a potent candidate for the treatment and prevention of colorectal cancer.
Highlights
The surplus amount of lipids in obesity is one of the biggest public health problems facing the world today
Oroxylin A modulated lipid metabolism of colon cancer cells stimulated with PA under hypoxia
By oil red staining and nile red staining, we found that hypoxia condition induced lipid droplet (LD) accumulation (Supplementary Figures S1A and S1B)
Summary
The surplus amount of lipids in obesity is one of the biggest public health problems facing the world today. Some of the pyruvate is converted to acetyl-CoA, which, in turn, is used in de novo fatty acid synthesis.[8] Highly proliferating cancer cells need to synthesize fatty acids de novo to continually provide lipids for membrane production and energy production through β-oxidation and lipid modification of proteins, which act as second messengers regulating signaling pathways, as well as participating in protein posttranslational modification.[9,10] Just a small shift in the regulation of lipid metabolism can lead to a large change in energy homeostasis; it can result in excess fat accumulation and it may affect many important cellular processes, including cell growth, proliferation and differentiation.[11]. We demonstrated fatty acid metabolism-facilitated colon cancer progression, and found that OA modulated fatty acid metabolism through HIF1α, inducing the inactivation of the Wnt signaling pathway and cell growth inhibition of colon cancer
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