Abstract
Although disruptions in the maintenance of iron and cholesterol metabolism have been implicated in several cancers, the association between variants in the HFE gene that is associated with cellular iron uptake and cholesterol metabolism has not been studied. The C282Y-HFE variant is a risk factor for different cancers, is known to affect sphingolipid metabolism, and to result in increased cellular iron uptake. The effect of this variant on cholesterol metabolism and its possible relevance to cancer phenotype was investigated using wild type (WT) and C282Y-HFE transfected human neuroblastoma SH-SY5Y cells. Expression of C282Y-HFE in SH-SY5Y cells resulted in a significant increase in total cholesterol as well as increased transcription of a number of genes involved in its metabolism compared to cells expressing WT-HFE. The marked increase in expression of NPC1L1 relative to that of most other genes, was accompanied by a significant increase in expression of NPC1, a protein that functions in cholesterol uptake by cells. Because inhibitors of cholesterol metabolism have been proposed to be beneficial for treating certain cancers, their effect on the viability of C282Y-HFE neuroblastoma cells was ascertained. C282Y-HFE cells were significantly more sensitive than WT-HFE cells to U18666A, an inhibitor of desmosterol Δ24-reductase the enzyme catalyzing the last step in cholesterol biosynthesis. This was not seen for simvastatin, ezetimibe, or a sphingosine kinase inhibitor. These studies indicate that cancers presenting in carriers of the C282Y-HFE allele might be responsive to treatment designed to selectively reduce cholesterol content in their tumor cells.
Highlights
Cellular iron uptake is regulated by a number of proteins including HFE that when mutated are associated with increased cellular iron uptake and a host of intracellular changes [1]
Biochemical assessment of cholesterol content indicated that C282Y-HFE expressing cells had,18% more cholesterol than wild type (WT)-HFE cells (Figure 1A)
We found that C282Y-HFE neuroblastoma cells have increased cholesterol compared to WT-HFE neuroblastoma cells
Summary
Cellular iron uptake is regulated by a number of proteins including HFE (high iron) that when mutated are associated with increased cellular iron uptake and a host of intracellular changes [1]. The wild type (WT)-HFE protein interacts with the transferrin receptor (TfR) to limit uptake of iron-loaded transferrin into the cell. In contrast to plasma membrane-associated WT-HFE, the C282Y-HFE mutant protein is retained in the endoplasmic reticulum (ER) where it does not interact with TfR failing to limit iron uptake [2,3]. A number of studies have shown that C282Y-HFE is associated with accumulation of iron at both the cellular and tissue level [4,5]. The presence of lower TfR levels in C282Y-HFE cells is an indicator of iron-overload as the cells try to limit further iron uptake by reducing TfR expression [5]. Because of the association of the C282Y-HFE mutation with cellular iron-overload it is logical to propose that the C282Y-HFE gene may be linked to diseases in which iron dysregulation occurs, such as cancer.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
