High Exogenous Cholesterol Level Suppress the HMGCR Expression in MVA Pathway and it's Relationship with Ferroptosis in Colorectal Cancer cell

Abstract

Ferroptosis is a type of programmed cell death that can be regulated in many pathways to interfere with the development of many diseases such as tumors. Based on the recent years study, the mevalonate (MVA) pathway has been discovered to be one of the significant regulatory factors of ferroptosis. In addition, hydroxymethylglutaryl coenzyme A reductase (HMGCR), a crucial regulatory enzyme manipulating the biosynthesis of endogenous cholesterol, found out to be the rate-limiting enzyme of MVA pathway by previous studies. However, despite HMGCR being known to be highly contributing to cholesterol biosynthesis, interplay of MVA pathway and HMGCR expression affected by the cholesterol level remains unexplored. In this research, we focused on colorectal cancer by using HT29 cell line as the target of study and we hypothesize that by increasing the concentration of exogenous cholesterol inhibit HMGCR will lead to the production of inhibitory effect on MVA Pathway. Isopentenyl Pyrophosphate (IPP) is an important product of the MVA Pathway, which the inhibition of MVA Pathway will result in the decrease of IPP production. The decrease of IPP production is impeding Selenocysteine tRNA maturation and downregulating the synthesis of Selenocysteine tRNA, which in turn is affecting Glutathione Peroxidase 4 (GPX4) activity. The GPX4 and Ferroptosis are also closely connected, so if GPX4 is inhibited, Ferroptosis is likely to occur and thus affect the progression of Colorectal cancer. With a more in depth understanding of the mevalonate pathway and its relationship with ferroptosis, it could propose a new target for antitumor treatment development in the future.