Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism

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.

Epistructured catechins, EGCG and EC facilitate apoptosis induction through targeting de novo lipogenesis pathway in HepG2 cells

“…However, cancer cells still have higher levels of FASN than those of lipogeneic tissues [ 17 ]. Overexpression of FASN in cancerous cells is regulated through multiple signaling pathways, including growth factor/growth factor receptors, such as the epidermal growth factor receptor (EGFR), human epidermal growth factor-2 (HER2), and hypoxia conditions [ 40 ]. FASN expression in cancer cells is also activated by activation of tumor suppressor gene downstream pathways, for example, phosphoinositide-3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase (MAPK) signaling pathways, leading to enhanced tumorigenesis [ 39 , 41 ].…”

Preparation and characterization of dummy molecularly imprinted polymers for separation and determination of farrerol from Rhododendron aganniphum using HPLC

“…Farrerol has a range of activities that are beneficial against cardiovascular diseases, respiratory system diseases, and Alzheimer's disease, and it has anti-inflammatory, antibacterial, hypoglycemic, antioxidant, anticancer, antitumor, immunity enhancing, and other pharmacological effects (9)(10)(11)(12)(13)(14). Many methods for extracting and detecting farrerol have been reported, including high-performance liquid chromatography and capillary electrophoresis (2,15,16), but these methods cannot provide the selectivity that is required for effective extraction and determination of bioactive components from complex matrices.…”

Tanshinone IIA reduces secretion of pro‑angiogenic factors and inhibits angiogenesis in human colorectal cancer

“…HIF-1α associates with hypoxia response element (HRE), forming the response element binding protein and activating the formation of complexes of other transcription factors. HIF-1α has been revealed to upregulate expression of VEGF and bFGF (24,25), and upregulation of HIF-1α in CRC tissues during hypoxic conditions enabled the survival of tumor cells and potentiated evolution of tumors (26,27). Proliferation of endothelial cells underlies the formation of blood vessels and thus is required for angiogenesis, both physiologically and pathophysiologically in tumor tissues.…”