Characterization of the modulatory effect of zeaxanthin isolated from maize kernels on cellular signaling pathways associated with hyperglycemia-induced HepG2 cell proliferation

Abstract

Background

Carotenoids are the group of antioxidant phytonutrients, found to repress carcinogenesis by modulating multiple cellular signaling pathways. Since diabetes patients have two to three folds increased risk of liver cancer, the present study aimed to explore the role of zeaxanthin on various molecular targets of high glucose-mediated human hepatocellular carcinoma (HepG2) cell proliferation.

Methods

The antiproliferative effect of zeaxanthin was examined by WST-1 assay. The DCFH-DA fluorescence dye was used to measure the intracellular ROS levels. The modulatory effect of zeaxanthin on the protein expression of MAPK-p38, Akt, and ERK, and antioxidant markers such as Nrf2, SOD2, HO1, and catalase, and apoptosis markers, Bcl2, P53, and cleaved caspase 3 was measured by western blotting. Apoptosis-inducing effect of zeaxanthin in high glucose subjected HepG2 cells was examined using DAPI staining.

Results

Zeaxanthin exhibits an effective growth inhibition in high glucose subjected HepG2 cells. It drastically repressed high glucose-mediated elevation of ROS levels. Further, zeaxanthin suppressed hyperglycemia-mediated ROS-driven p38 activation to mitigate HepG2 cell proliferation. Zeaxanthin also switched on the apoptosis pathway in hyperglycemic HepG2 cells. The apoptosis induction by zeaxanthin was confirmed with downregulated Bcl2 and P53 and upregulated cleaved caspase 3 protein expression.

Conclusions

The current findings substantiate the previous findings that zeaxanthin has greater potential than lutein in sensitizing hyperglycemic HepG2 cells by modulating multiple signaling pathways. The study highlights the importance of zeaxanthin as a powerful phytonutrient which possesses chemotherapeutic potential against diabetes-associated liver cancer progression.