Hyperglycaemia-induced human hepatocellular carcinoma (HepG2) cell proliferation through ROS-mediated P38 activation is effectively inhibited by a xanthophyll carotenoid, lutein.

Aims: Diabetic population have a twofold to threefold increased risk of developing
liver cancer, and hyperglycaemia is a prime causative factor that propends
the tumour cells to undergo aggressive metabolic growth. In this study, we aimed
to examine the molecular mechanism by which lutein inhibits hyperglycaemia-induced
human hepatocarcinoma (HepG2) cell proliferation.
Methods: The effect of lutein on high glucose-induced
proliferation was measured
using the WST-1
reagent. Its effect on intracellular reactive oxygen species
(ROS) levels was measured by DCF assay. The effect on the expression of antioxidant
enzymes, cell cycle regulatory proteins and intracellular protein kinases was
analysed by western blotting. The modulatory effect of lutein on different phases
of the cell cycle was analysed by flow cytometry.
Results: The data showed that lutein at 5 μM concentration significantly blocked
glucose-promoted
HepG2 cell proliferation. Suppression of high glucose-induced
cell proliferation by lutein was not associated with apoptosis induction, but it was
linked with inhibition of hyperglycaemia-mediated
elevated ROS and upregulated
expression of high glucose-mediated
repressed heme oxygenase 1 (HO1).
Furthermore, G2/M phase cell cycle arrest and associated phosphorylation of
Cdk1 and P53 were found to be linked with suppressed hyperglycaemia-mediated
cell proliferation by lutein. In addition, lutein inhibited hyperglycaemia-induced
activation of P38 which relates to high glucose-induced
ROS-mediated
growth
suppression and modulated the phosphorylation of Erk, JNK and Akt in hyperglycaemic
HepG2 cells.
Conclusion: Our findings portray that sufficient intake of lutein may offer a negative
impact on diabetes-associated
tumour growth.