Title:Antitumoral Alkylphospholipids Alter Cell Lipid Metabolism
Volume: 14
Issue: 4
Author(s): Carmen Marco, Pablo Ríos-Marco, Jose M. Jiménez-López, Josefa L. Segovia and María P. Carrasco
Affiliation:
Keywords:
Alkylphospholipids, cholesterol homeostasis, HepG2 cells, phospholipid metabolism.
Abstract: Alkylphospholipid (APL) analogues are promising candidates in the search for treatments for cancer. In contrast to standard
chemotherapeutic drugs, these lipophilic agents target the cell membrane without interacting directly with DNA. A variety of
mechanisms have been suggested to explain the actions of these compounds, which can induce apoptosis and/or cell growth arrest. In this
review, we focus on recent advances in our understanding of the actions of clinically-relevant APLs, such as hexadecylphosphocholine
(HePC), edelfosine, erucylphosphocholine (ErPC) and perifosine on the human hepatoma HepG2 cell line, which is commonly used for
lipid metabolism studies with a special emphasis on cholesterol metabolism.
One consistent finding is that HePC and other APLs cause a reduction in the biosynthesis of phosphatidylcholine (PC) by inhibiting the
rate-limiting enzyme CTP:phosphocholine cytidylyltransferase (CT). Our research group has been at the forefront in demonstrating that
exposure to APLs affects cholesterol homeostasis in mammalian cells. Treatment with HePC, for example, causes a marked enhancement
in cholesterol synthesis, which has been related to an impairment in the arrival of cholesterol at the endoplasmic reticulum (ER). In a
similar way to HePC, edelfosine, ErPC and perifosine increase the de novo synthesis and uptake of cholesterol and also inhibit the arrival
of plasma-membrane cholesterol at the ER, which induces a significant cholesterogenic response in these cells, involving an increase in
gene expression and higher levels of several proteins related to the biosynthetic pathway and receptor-mediated uptake of cholesterol.
It is generally accepted nowadays that the maintenance of a tightly controlled free-cholesterol/PC ratio is crucial to optimum cell
behaviour and that alterations to this ratio may lead to necrosis and/or apoptosis. Our results have considerable bearing on this idea
because an increase in cholesterol biosynthesis associated with a decrease in the synthesis of choline-containing phospholipids and
cholesterol esterification leads to a modification in the free-cholesterol/PC ratio in cells exposed to APLs. It is well accepted that
cholesterol is critical for the formation of lipid rafts and therefore drugs that alter cell cholesterol content should modify the properties of
these membrane domains and consequently the signal-transduction pathways, which depends upon lipid-raft integrity. Results on the
whole show that APLs share a common active mechanism consisting of disrupting PC and sphingomyelin (SM) biosyntheses and
cholesterol homeostasis, all of which leads to a disturbance in the native membrane structure, thus affecting signaling processes vital to
cell survival and growth.
