LOW DENSITY LIPOPROTEIN

INTRODUCTION
Cholesterol is a fat-like molecule that our cells produce and utilise
for structure, as well as to manufacture vitamin D, hormones, and
bile acids, all of which are essential for digestion[1].Cholesterol
plays a vital role in cancer development. It is an important
component of lipid rafts, which are the crucial platforms for
signaling regulation in cancer, and chelating membrane
cholesterol is an efficient anti-cancer strategy that disturbs the
functions of lipid rafts[2].
Cholesterol metabolism is usually reprogrammed in cancer cells.
On the one hand, raised cholesterol levels are linked with a higher
cancer incidence, and cholesterol-lowering drugs e.g., statins
show advantageous effects by lessening the risk and mortality of
breast cancer, prostate cancer, and colorectal cancer; on the other
hand, cancers such as bladder cancer and lung cancer are not
related with cholesterol levels, and statins may exhibit
carcinogenic properties[2].
Cholesterol moves within the body in the bloodstream in packages
known as lipoproteins, of which there are two principal types: low-
density lipoprotein (LDL) and high-density lipoprotein (HDL).
These proteins are usually referred to as “bad” and “good”
cholesterol, respectively[3].
Cholesterol is principally manufactured in the liver and carried to
cells around the body by the bloodstream as an LDL-bound form.
LDL is taken inside cells by clathrin-mediated endocytosis and
transported to the lysosomes by the endocytic pathway, where it
is later hydrolyzed to free cholesterol molecules, which are

shuttled to the cell membrane and another cell membrane-bound
organelles[4].

HYPERCHOLESTEROLEMIA AND CANCER
Elevated serum cholesterol levels have been described to be
positively associated with a higher risk of developing cancers, such
as colon cancer, prostatic cancer, rectal cancer, and testicular
cancer. A meta-analysis proposed that dietary cholesterol
consumption enhances the risk of breast cancer[2]. Observations
based on cancer models support the positive association between
hypercholesterolemia and carcinogenesis[2]. Despite these
positive associations between hypercholesterolemia and
carcinogenesis, some epidemiologic researches suggest that no
relationship exists between cholesterol and cancer progression[5].
In general, clinical studies and animal tests suggest that
hypercholesterolemia may have a role in some forms of cancer,
such as breast and prostate cancer. However, because of
conflicting findings regarding the link between
hypercholesterolemia and cancer, the relationship between
cholesterol and cancer may not be a simple two-factor association,
and the possibility of a conditional factor capable of reversing the
correlation between cholesterol and cancer progression is worth
considering[2].
The cancer’s tissue origin might be a third conditional factor.
Varying tissues have different cholesterol requirements and
component ratios. Another conditional element may be cholesterol
consumption regularly, and differing dietary habits could be an
epigenetic regulator impacting cancer development[2].

CHOLESTEROL CAN DIRECTLY ACTIVATE ONCOGENIC
SIGNALLING

As an essential component of the cell membrane, cholesterol may
be closely linked to membrane receptors through which
cholesterol could directly stimulate oncogenic signaling[2].
The Hedgehog pathway is a well-known cancer-related signalling
system that is regulated by the Smoothened receptor, a G-
protein-coupled receptor (GPCR)[5]. Cholesterol has been shown
to stimulate oncogenic Hedgehog signalling by binding directly to
the Smoothened receptor, according to two studies[7].
Signaling activity is linked to cell differentiation, cell proliferation,
and tumour development[2].
Cholesterol also has a role in the cytoplasm, in addition to the cell
membrane. Lysosomal cholesterol has been found to activate
mTORC1 via the SLC38A9-Niemann-Pick C1 signalling complex in
recent investigations. Activation of mTORC1 promotes cell
proliferation, invasion, and metastasis[8].

LIPID RAFTS
Lipid rafts are special small lipid domains within the cell
membrane that are rich in cholesterol and sphingolipids. Lipid
rafts are platforms for cellular signal transduction, and their
structure and function depend on the composition of cholesterol
and related phospholipids[2]. Variations in membrane cholesterol
and cholesterol-rich membranes have been displayed to influence
cancer progression and invasion[9].
Lipid rafts also provide a signal transduction platform for
oncogenic signaling pathways. Changes in cholesterol levels can

cause structural damage to lipid rafts, which can either activate or
inhibit raft-related proteins including death receptor proteins,
protein kinases, and calcium channels. Akt is a well-known
serine/threonine protein kinase that plays a key function in
regulation of cancer cell survival and may be activated more
efficiently when translocated to lipid raft regions[2].
Various invasive cancer cells can form invadopodia, which can
induce degradation. Lipid rafts are required for invadopodia
formation in breast cancer cells and extracellular matrix (ECM)
degradation[10].

CHOLESTEROL INFLUX
Through receptor-mediated processes, low-density lipoprotein
(LDL) particles transfer cholesterol to most surrounding tissues
[11]. Cancer patients’ lipid profiles are said to show lower plasma
lipoprotein levels, which return to normal following tumour
remission, underlining the relevance of lipoproteins in tumour
growth and progression[12].
Because the activation of these pathways is mostly connected to
cell development, elevation of intracellular cholesterol levels can
be accomplished via constitutive activation of PI3K/AKT/mTOR
signalling, activation of SREBP, or stimulation of LDL receptor-
mediated cholesterol inflow[2].

CHOLESTEROL EFFLUX
A membrane transfer protein called ATP-binding cassette
transporter A1 (ABCA1) may transport cholesterol from the
intracellular compartment to the extracellular environment[13].

Overexpression of mutant TP53 and Ras has been shown to slow
the development of xenograft tumours by blocking ABCA1, which
leads to an increase in mitochondrial cholesterol levels[2].
According to one study, cancer-specific ABCA1 hypermethylation
and ABCA1 expression downregulation resulted in elevated
intracellular cholesterol levels, contributing to the formation of a
cancer-friendly environment[2].

Although some studies suggest that a very low level of LDL can
heighten the cancer risk, more research is needed on this topic to
confirm the same[14].