Bergapten inhibits liver carcinogenesis by modulating LXR/PI3K/Akt and IDOL/LDLR pathways

Abstract

Oxysterol receptors LXRs (α and β) are recently reported to be one of the novel and potential therapeutic targets in reducing cell proliferation and tumor growth in different system model. Activation of LXRs is correlated with modification of PI3K/Akt pathway. LXRs are also found to play a critical role in maintaining lipid homeostatais by regulating ABCA1, IDOL, SREBP1, LDLR and also certain lipogenic genes such as FASN and SCD1. In the present study a potential furanocoumarin, Bergapten (BeG) has been evaluated for its anticancer property on Hepatocellular Carcinoma (HCC) on LXR axis. The molecular docking analysis was carried out for BeG on LXR (α & β) using Maestro tool and compared with reference ligands. This was followed by in vitro (HepG2 cell lines) and in vivo (on NDEA induced HCC in Wistar albino rats) anticancer evaluation of BeG. The docking results revealed polar and hydrophobic interactions of BeG with LXR (α,β). The in vitro studies revealed the potential of BeG in lowering the accumulation of lipid droplets in HepG2 cells which was correlated with increase in LXR (α,β) protein expressions. Furthermore, the in vivo studies demonstrated the potential of BeG in ameliorating the cancer induced alterations in body weight, liver weight and significant restoration of the changes in mRNA and protein expressions of LXR(α,β), ABCA1, IDOL, SREBP1 and LDLR. BeG also modulated the expressions of PI3K, Akt and certain lipogenic genes like FASN and SCD1 and reduced the lipid droplets level in liver cancer cells. These results provide evidence and validates the critical role of BeG in maintaining the lipid homeostasis and justifies its anticancer potential against NDEA-induced HCC.

Anticancer Potential of Furanocoumarins: Mechanistic and Therapeutic Aspects

“…In apoptosis, cytosol Bax releases caspase-activating Cyt-c. The caspase-8 (extrinsic apoptosis) or -9 (intrinsic apoptosis), is activated which further activates caspase-3, essential to propagates apoptotic signal [49][50][51][52][53]. Cell shrinkage and chromatin condensation helps in apoptosis [54].…”

“…Highly expressed SREBPs play important roles in malignancies, connecting oncogenic signaling to lipid metabolism alterations, leading to rapid tumor growth. PI3K-Akt pathway is inhibited by LXRs [53,75]. Bergapten inhibits liver carcinogenesis (HepG2) by activating LXRs, inhibiting PI3K/Akt that reduced SREBP-1, fatty acid synthase (FASN), stearoyl-CoA desaturase-1 (SCD1), thereby preventing fatty acid synthesis and tumor growth [53].…”

“…N-nitrosodiethylamine (NDEA) causes oxidative stress and responsible for the carcinogenic effect. Bergapten has shown to possess anticancer potential in vivo against NDEA-induced liver cancer via antioxidant effects [53]. Hypoxia is a noteworthy component of tumor malignant growth, and it activates hypoxia inducible factor (HIF), thus increasing tumor survival and proliferation [85].…”

Inhibitory Effects of Furanocoumarins From the Roots ofAngelica dahuricaon Ionizing Radiation-Induced Migration of A549 Human Non-Small Cell Lung Cancer Cells

“…In several published studies, compounds 1-3 have shown potent anticancer activity in numerous cancer cell lines but these have not included lung cancer. [28][29][30][31][32][33] For example, psoralen (1) inhibited proliferation by modulating the Wnt/β-catenin pathway in breast cancer cells. 28 Xanthotoxin (2) has been reported to possess antitumor activity in breast cancer cells 29 and inhibits the activation of AP-1 and NF-κB subunits.…”

IDOL gene variant is associated with hyperlipidemia in Han population in Xinjiang, China

“…Numerous animal studies showed that overexpression of IDOL gene in mouse liver caused the development of hypercholesterolemia and atherosclerosis 8 . Instantaneous adenoviral overexpression of mouse IDOL gene in wildtype model resulted in a significant decrease in LDLR protein and an increase in LDL-C levels 9,10 . Other possible downstream of IDOL includes VLDLR and ApoER2 11 .…”