M I N I R E V I E W

Lipid metabolism in cancer

Claudio R. Santos

1

and Almut Schulze

2

1 Translational Cancer Therapeutics, Cancer Research UK London Research Institute, UK

2 Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, UK

Keywords

Akt signalling; cancer; fatty acid synthesis;

hypoxia; lipid metabolism

Correspondence

Claudio R. Santos, Translational Cancer

Therapeutics, Cancer Research UK London

Research Institute, 44 Lincoln’s Inn Fields,

London WC2A 3LY, UK

Fax: [phone]

Tel: [phone]

E-mail: [e-mail]

(Received 31 January 2012, revised 10 May

2012, accepted 16 May 2012)

doi:10.1111/j.1742-4658.2012.08644.x

Lipids form a diverse group of water-insoluble molecules that include tria-
cylglycerides, phosphoglycerides, sterols and sphingolipids. They play sev-
eral important roles at cellular and organismal levels. Fatty acids are the
major building blocks for the synthesis of triacylglycerides, which are
mainly used for energy storage. Phosphoglycerides, together with sterols
and sphingolipids, represent the major structural components of biological
membranes. Lipids can also have important roles in signalling, functioning
as second messengers and as hormones. There is increasing evidence that
cancer cells show specific alterations in different aspects of lipid metabo-
lism. These alterations can affect the availability of structural lipids for the
synthesis of membranes, the synthesis and degradation of lipids that con-
tribute to energy homeostasis and the abundance of lipids with signalling
functions. Changes in lipid metabolism can affect numerous cellular pro-
cesses, including cell growth, proliferation, differentiation and motility.
This review will examine some of the alterations in lipid metabolism that
have been reported in cancer, at both cellular and organismal levels, and
discuss how they contribute to different aspects of tumourigenesis.

Deregulation of lipid metabolism in cancer

Most adult mammalian cells acquire lipids from the
bloodstream either as free fatty acids or complexed to
proteins such as low-density lipoproteins. These lipids
are obtained from dietary sources or are carbohydrate-
derived fatty acids synthesized in the liver or in adipo-
cytes, where they can also be stored in intracellular
structures called lipid droplets.

De novo

fatty-acid biosynthesis in the adult organ-

ism occurs mainly in the liver, adipose tissue and the
lactating breast. The acetyl groups for fatty-acid bio-

synthesis are provided mainly by citrate, which is
produced

by

the

tricarboxylic

acid

(TCA)

cycle

(Fig. 1). The conversion of citrate into acetyl-coenzyme
A (acetyl-CoA) and oxaloacetate is catalysed by aden-
osine triphosphate (ATP)-citrate lyase. Oxaloacetate
can be converted into pyruvate by malic enzyme. This
reaction

generates

NADPH

and,

along

with

the

NADPH-producing

reactions

in

the

pentose

phosphate pathway, provides the reducing power for
lipid synthesis.

Abbreviations

ACACA and ACACB, isoforms of acetyl-CoA carboxylase; ACC, acetyl-CoA carboxylase; AMPK, 5

¢ adenosine monophosphate-activated

protein kinase; ATP, adenosine triphosphate; CoA, coenzyme A; FADH

2,

flavin adenine dinucleotide (hydroquinone form); FASN, fatty acid

synthase; GLUT1, glucose transporter 1; HIF, hypoxia-inducible factor; HMG, 3-hydroxy-3-methylglutaryl; HMGCR, 3-hydroxy-3-methylglutaryl

coenzyme A reductase

⁄ HMGCR-CoA reductase; IGF1, insulin-like growth factor 1; LPA, lyophosphatidic acid; MAGL, monoacylglycerol

lipase; mTORC1, mammalian target of rapamycin complex I; PDK, pyruvate dehydrogenase kinase; SCAP, SREBP cleavage-activating

protein; SCD, stearoyl-CoA desaturase; SREBP, sterol regulatory element-binding protein; TCA, tricarboxylic acid; VHL, Von Hippel–Lindau.

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The

committed

step

of

fatty-acid

biosynthesis

requires the activation of acetyl-CoA to malonyl-CoA.
This is an energy-consuming process catalysed by ace-
tyl-CoA carboxylase (ACC). The acetyl and malonyl
groups are then coupled to the acyl-carrier protein
domain of the multifunctional enzyme fatty-acid syn-
thase (FASN). Repeated

condensations of

acetyl

groups generate basic 16-carbon saturated fatty acids
(palmitic acid).

Further elongation and desaturation of newly syn-

thesized fatty acids takes place at the cytoplasmic face
of the endoplasmic reticulum membrane. Fatty acids

with longer chains, such as stearic acid, are obtained
through the action of a family of enzymes (‘elongation
of very-long-chain fatty-acid proteins’) that add two
carbons to the end of the chain in each cycle of reac-
tions.

This

family

comprises

seven

members

(ELOVL1–7) with different chain lengths and satura-
tion specificities.

Desaturation is catalysed by fatty acyl-CoA desatu-

rases, which include the stearoyl-CoA desaturases
(SCDs). SCD1 introduces a double bond in the D9
position of palmitic and stearic acids to produce
mono-unsaturated fatty acids. Fatty acyl-CoA desatu-

Fig. 1. Regulation of lipid metabolism by oncogenic signalling pathways. Many cancer cells show high rates of de novo lipid synthesis. Fatty

acids are required for the production of phosphoglycerides, which, together with cholesterol, can be used for building cell membranes. Tria-

cylglycerides and cholesterylesters are stored in lipid droplets. Lipids from extracellular sources can also be used for these purposes. Fatty

acids mobilized from lipid stores can be degraded in the mitochondria through b-oxidation to provide energy when required. Many enzymes

within the fatty-acid and cholesterol-biosynthesis pathways are regulated by SREBPs (highlighted by yellow boxes). Oncogenic activation of

the PI3K

⁄ Akt pathway promotes glucose uptake and its use in lipid synthesis through activation of SREBP. Activation of E2F following loss

of the retinoblastoma protein increases expression of SREBPs and their target genes. Mutant p53 (p53mut) increases the expression of

genes within the cholesterol biosynthesis (mevalonate) pathway by binding to their promoters. AMPK is activated in response to low cellular

energy levels and prevents lipid synthesis and stimulates b-oxidation through inhibition of ACC. AMPK can also inhibit SREBP by direct phos-

phorylation. Activation of HIF1 by hypoxia reduces the flux of glucose to acetyl-CoA through the mitochondria. Reductive metabolism of

glutamine-derived a-ketoglutarate provides cytoplasmic citrate in hypoxic cells. ACAT, acetyl-CoA acetyltransferase; ACLY, ATP citrate lyase;

ACSL, acyl-CoA synthetase long-chain; CPT1, carnitine palmitoyltransferase; ETC, electron transport chain; HMGCS, HMG coenzyme A

synthase; IDH, isocitrate dehydrogenase; MCT, monocarboxylate transporter; pRB, retinoblastoma 1.

C. R. Santos and A. Schulze

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rases catalyse the synthesis of highly unsaturated fatty
acids from essential polyunsaturated fatty acids, which
are mainly derived from the diet. Desaturation alters
the physical properties of long-chain fatty acids,
including those used for the synthesis of membrane
phosphoglycerides, and is an important determinant of
membrane fluidity. Fatty acids can also be used for
energy storage in the form of triacylglycerides. These
are composed of three fatty-acid chains of different
chain length and saturation bound to a glycerol mole-
cule via ester bonds.

It was noted, over 50 years ago, that neoplastic

tissues are able to synthesize lipids [1] in a manner simi-
lar to embryonic tissues (in this issue of FEBS, Altam &
Dang discuss the similarities between the metabolism of
tumour cells and that of normal proliferating cells, using
T cells as an example). In 1996, Kuhajda and colleagues
showed that OA-519, a prognostic marker in breast can-
cer, corresponds to FASN [2]. Since then, several studies
have shown that tumour cells reactivate de novo lipid
synthesis ([3] and references therein). Some cancers,
including breast and prostate [4–6], show increased
expression of FASN, which suggests that fatty-acid syn-
thesis plays an important role in cancer pathogenesis [3].
Furthermore, it has been shown that ATP-citrate lyase
is required for cell transformation in vitro and for
tumour formation in vivo [7,8], and chemical inhibition
of ACC induces growth arrest and apoptosis in prostate
cancer cells [9]. The long-chain fatty-acid elongase
ELOVL7 was shown to be overexpressed in prostate
cancer and required for prostate cancer-cell growth,
possibly because of its role in the synthesis of steroids,
such as androgens [10], and although overexpression of
elongases has not been reported in other tumours, it is
worth noting that overexpression of oncogenic Ras has
been shown to increase the levels of very-long fatty-acid
chains [11,12], suggesting that they may play a yet-
unknown role in transformation.

Another important biosynthetic process within lipid

metabolism is the mevalonate pathway, which facili-
tates the synthesis of cholesterol (Fig. 1). The first
steps of cholesterol biosynthesis involve the condensa-
tion of acetyl-CoA with acetoacetyl-CoA to form
3-hydroxy-3-methylglutaryl (HMG)-CoA. The reduc-
tion of HMG-CoA to mevalonate by HMG-CoA
reductase (HMGCR) represents the rate-limiting reac-
tion of the cholesterol synthesis pathway and is highly
regulated. HMGCR is an endoplasmic reticulum-trans-
membrane protein and its stability is regulated by a
sterol-sensing-domain that mediates its degradation
under saturating sterol levels [13]. Cholesterol is an
important component of biological membranes as it
modulates the fluidity of the lipid bilayer and also

forms detergent-resistant microdomains called lipid
rafts that coordinate the activation of some signal-
transduction pathways [14]. The cholesterol biosynthesis
pathway also generates intermediates required for the
isoprenylation of small GTPases, including the farnesy-
lation of Ras and the geranyl-geranylation of Rho
[15]. Finally, sterols have an important role in organis-
mal development as they form the structural backbone
for the synthesis of steroid hormones.

Accumulation of cholesterol has been reported in

prostate cancer [16] and deregulation of the mevalo-
nate pathway has been associated with transformation
[17]. Interestingly, HMGCR is the target for a class of
cholesterol-lowering drugs known as statins. Statins
show antiproliferative activity in several cancer-cell
lines, with the described effects ranging from cell cycle
arrest (e.g. in breast cancer cells [18,19]) to apoptosis
(e.g. in acute myeloid leukaemia [20]). Statins have
also been shown to increase the sensitivity of colorectal
cancer cells to chemotherapeutic agents through induc-
tion of epigenetic reprogramming [21], and indeed
combination of statins with chemotherapy has shown
promising results in clinical trials of patients with acute
myeloid leukaemia [22] and hepatocellular carcinoma
[23], among others. As millions of patients throughout
the world are treated with statins to lower cholesterol,
this has raised the question of whether its use may be
associated with a decreased incidence of cancer.
A multitude of epidemiological analyses, mainly retro-
spective, have been published in the last few years but
a conclusive answer is yet to be found. The effect of
statins on cancer incidence seems to be highly depen-
dent on the tumour type and class of statins used. For
example, several meta-analyses found either no effect
or a small, nonsignificant trend towards a protective
effect of statins against colon cancer [24–26]. Other
studies found a significant protective effect in hepato-
cellular carcinoma [27] or in patients treated with a
lipophilic statin after being diagnosed with breast can-
cer [28]. There are currently a number of ongoing pro-
spective studies that should help to finally resolve this
question.

Triacylglycerides and cholesterylesters are stored in

lipid droplets, highly ordered intracellular structures
that are formed from the endoplasmic reticulum
through a budding process [29]. They are composed of
a phospholipid and sterol monolayer containing spe-
cific proteins and a core of nonpolar lipids. Cancer
cells seem to contain increased numbers of lipid drop-
lets compared with normal tissue. This was observed
in colon adenocarcinomas or intestinal epithelial cells
after transformation with H-ras V12 [30]. The same
study demonstrated that cyclooxygenase 2 and prosta-

Lipid metabolism in cancer

C. R. Santos and A. Schulze

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glandin synthase localize to lipid droplets in cancer
cells, suggesting that these structures could be involved
in regulating cancer pathogenesis [30].

Triacylglycerides provide a reservoir of fatty acids

that can be mobilized for energy generation through
the action of a series of lipases, such as hormone-sensi-
tive lipase, adipose triglyceride lipase and monoacyl-
glycerol lipase (MAGL). Cytoplasmic free-fatty acids
are then coupled to CoA and the acyl chain is trans-
ferred to carnitine by carnitine acyltransferase to be
transported into the mitochondrial matrix (Fig. 1).
After entering the mitochondrial matrix, acyl chains
are recoupled to CoA and degraded by repeated
rounds of oxidation and hydration. This process is
known as b-oxidation and produces NADH and flavin
adenine dinucleotide (hydroquinone form) (FADH

2

) as

well as acetyl-CoA, which can enter the TCA cycle to
be completely oxidized. The mode of regulation of
b-oxidation ensures that lipid synthesis and degrada-
tion are mutually exclusive. The activity of carnitine
acyltransferase is inhibited by malonyl-CoA, produced
by ACC during fatty-acid biosynthesis. The two iso-
forms of ACC – ACACA and ACACB – differ in their
ability to be activated by citrate [31], and ACACB is
thought to be the main isoform responsible for inhibit-
ing b-oxidation. ACC is also a target for the 5

¢ adeno-

sine monophosphate-activated protein kinase (AMPK),
a heterotrimeric protein kinase that is activated in
response to low energy levels and inhibits energy-con-
suming processes while promoting energy production
[32]. AMPK phosphorylates and inhibits both ACACA
and ACACB, resulting in the inhibition of fatty-acid
synthesis and the induction of b-oxidation [33].

There are a number of studies that link b-oxidation

with cancer. Fatty-acid oxidation is a dominant path-
way for energy generation in prostate cancer [34] and
enhanced mitochondrial b-oxidation of fatty acids has
been linked to tumour promotion in pancreatic cancer
[35]. Inhibition of b-oxidation induces apoptosis in
leukaemia cells and in glioblastoma cells [36,37]. Phar-
macological activation of b-oxidation can also rescue
the glucose dependency of Akt-transformed cells [38],
suggesting that this pathway can provide important
metabolites for cancer-cell survival.

Activation of oncogenic pathways
stimulates lipid synthesis

Most enzymes involved in fatty-acid and cholesterol
biosynthesis are regulated by the sterol regulatory ele-
ment-binding

proteins

(SREBPs)

[39,40]

(Fig. 1).

SREBPs are transcription factors of the helix-loop-
helix leucine zipper family. They are translated as 125-

kDa precursors that are inserted into the endoplasmic
reticulum membrane where they are bound by the
SREBP cleavage-activating protein (SCAP). Three
SREBP isoforms – SREBP1a, SREBP1c and SREBP2
– have been identified in mammalian cells [41].
SREBP1a and SREBP1c are generated by alternative
splicing and vary in their expression levels across dif-
ferent tissues, with SREBP1a being the most abundant
isoform in most cultured cell lines [42]. Although there
is overlap between their target genes, SREBP1 mainly
regulates fatty acid, phospholipid and triacylglycerol
synthesis, while SREBP2 controls the expression of
cholesterol-synthesis genes [39].

The activity of SREBPs is tightly regulated by the

concentration of intracellular sterols. When sterol levels
are low, the SREBP

⁄ SCAP complex can associate with

COPII-coated vesicles and translocate to the Golgi
where a two-step proteolytic cleavage releases the 65-
kDa N-terminal transcriptionally active fragment. This
mature protein can then enter the nucleus and regulate
transcription by binding to sterol-regulatory elements
within the promoter regions of SREBP target genes [43].
When cellular cholesterol concentrations reach saturat-
ing levels, association of the SREBP

⁄ SCAP complex

with COPII is inhibited as a result of binding of the
insulin-induced gene, and the complex is retained in the
endoplasmic reticulum [44]. This classic model of sterol-
dependent regulation applies mainly to SREBP2 and
has been termed ‘regulated intramembrane proteolysis’
[45]. It is conserved between flies and mammals. How-
ever, SREBP processing in Drosophila is regulated by
phosphatidylcholine

and

phosphatidylethanolamine

rather than by sterols [46]. Interestingly, it has recently
been shown that depletion of phosphatidylcholine in
mammalian cells leads to nuclear accumulation of
SREBP1, but not of SREBP2, even in the presence of
cholesterol and through a SCAP-independent mecha-
nism [47], suggesting that phospholipid levels may be
the main regulators of SREBP1.

In addition to the regulation by proteolysis, the activ-

ity of SREBP transcription factors is modulated by
their interaction with transcriptional co-activators such
as p300 or cyclic adenosine monophosphate response
element-binding-binding

protein

[48].

SREBP

can

also associate with the activator-recruited co-factor

⁄

mediator complex to activate specific target genes [49].
Furthermore, SREBPs carry a cdc4 phospho-degron
motif and can be phosphorylated by glycogen synthase
kinase 3, resulting in polyubiquitination and degrada-
tion of the mature protein [50, 51].

The Phosphoinositide 3-kinase

⁄ Akt ⁄ PKB (protein

kinase B) signalling pathway is frequently activated in
human cancer [52]. Insulin stimulates lipid synthesis and

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ACC activity in liver and adipose tissue [53] and Akt can
phosphorylate ATP-citrate lyase [54] and activate the
expression of several genes involved in cholesterol and
fatty-acid biosynthesis [55]. One important downstream
effector of Akt is mammalian target of rapamycin com-
plex I (mTORC1), a multiprotein kinase involved in the
regulation of several metabolic processes, including pro-
tein synthesis [56]. The activity of mTORC1 is also regu-
lated by specific amino acids (reviewed by Richard F.
Lamb in this issue of FEBS). Interestingly, mTORC1
activity is required for the nuclear accumulation of
mature SREBP1 in response to Akt activation [57], and
transcriptional profiling of cells deficient for the tuber-
ous sclerosis complex 1 or 2 genes, two negative regula-
tors of mTORC1, revealed that SREBP is an important
component of the metabolic regulatory network down-
stream of this signalling axis [58]. mTORC1 also regu-
lates the expression of SREB1F and is required for the
stimulation of lipogenesis in the liver [59]. SREBP func-
tion is also essential for Akt-dependent regulation of cell
size, both in mammalian cells and in the developing
wing of Drosophila melanogaster [57], suggesting that
the Akt

⁄ mTORC signalling axis regulates protein and

lipid synthesis in a concerted manner during cell growth.

SREBP function is also downstream of several

tumour-suppressor pathways. AMPK, which is down-
stream of the liver kinase B1 tumour suppressor, can
directly phosphorylate SREBP, thereby preventing its
proteolytic activation [60]. Loss of the retinoblastoma
protein promotes the expression of genes involved in
the isoprenylation of N-Ras through induction of
SREBP1 and SREBP2 [61]. Furthermore, mutant
tumor protein p53 associates with SREBP at the pro-
moters of genes within the mevalonate pathway and
increases their expression [62]. This hyperactivation
disrupts tissue architecture and promotes the forma-
tion of breast cancer, placing SREBP-dependent lipo-
genesis at the core of the transformation process.

SREBP1 and SREBP2 are overexpressed in a num-

ber of cancers [3]. SREBP1 is activated by aberrant
epidermal growth factor receptor signalling in human
glioblastoma

multiforme,

albeit

independently

of

mTORC1 [63], and SREBP1-dependent induction of
low-density lipoprotein receptor expression is crucial
for the survival of these cancers [64]. These findings
demonstrate that activation of SREBP is an important
function of oncogenic signalling pathways in cancer.

Hypoxia and lipid metabolism

Solid tumours frequently present hypoxic areas as a
consequence of an increase in tumour volume that out-
grows the capacity of its vascular network. Low oxygen

availability leads to the activation of the hypoxia-
inducible factors (HIFs), two heterodimeric transcrip-
tion factors composed of an a-subunit (HIF1-a or
HIF2-a), and a b-subunit. Under normoxia, HIF-1a
and HIF-a are targeted by the oxygen-sensitive prolyl-
hydroxylases and are marked for degradation by Von
Hippel–Lindau (VHL) tumour suppressor-dependent
ubiquitination [65]. Mutations in VHL frequently occur
in renal cell carcinomas and promote a pseudo-hypoxic
state that leads to the stabilization of HIF1a and
HIF2a, even in the presence of oxygen [66]. HIFs can
also be activated by oncogenic pathways [67] and by
loss of p53 [68]. Interestingly, metabolic activity can
also contribute to HIF activity. Inactivating mutations
in the TCA cycle enzymes fumarate hydratase or succi-
nate dehydrogenase lead to the accumulation of succi-
nate, which blocks the activity of prolyl-hydroxylases
and results in the accumulation of HIF1a [69,70].

HIF activation not only promotes angiogenesis by

inducing expression of the vascular endothelial growth
factor [71], it also drives adaptation to the hypoxic
environment through a metabolic switch to anaerobic
energy production. HIF induces the expression of the
glucose transporter 1 (GLUT1) [72] and several glyco-
lytic enzymes [73]. HIF also prevents the entry of
pyruvate into the TCA cycle by inducing the expres-
sion of pyruvate dehydrogenase kinase 1 (PDK1), a
kinase that phosphorylates and inhibits pyruvate dehy-
drogenase [74], thereby preventing glucose-derived lipid
synthesis. However, it was demonstrated that HIF1
induces the expression of FASN in human breast-can-
cer cell lines and that FASN expression is increased in
hypoxic tumour regions [75]. Because the flow of car-
bon from glucose to fatty acids is attenuated by
hypoxia, other carbon sources are required to support
fatty-acid synthesis under these conditions. Indeed,
acetyl-CoA synthetase 2, the bidirectional enzyme
catalysing the synthesis of acetyl-CoA from cytoplas-
mic acetate, is induced by hypoxia and promotes can-
cer-cell survival under these conditions [76]. More
recently, three independent studies showed that gluta-
mine becomes the major carbon source for lipid syn-
thesis in the absence of functional mitochondria. These
studies found that isocitrate dehydrogenase-1 can pro-
duce cytoplasmic citrate by reductive carboxylation of
glutamine-derived

a-ketoglutarate.

This

metabolic

activity was found to be active in cancer cells with
defective mitochondria [77] and under hypoxia [78,79].

The inhibitory effect of hypoxia on b-oxidation has

been documented in different tissues. Ischaemia causes
reduced b-oxidation in the heart by preventing the oxi-
dation of NADH and FADH

2

[80], and exposure of

macrophages to hypoxic conditions results in enhanced

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C. R. Santos and A. Schulze

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storage of triacylglycerides [81]. HIF1 has been reported
to promote lipid accumulation through induction of the
hypoxia-inducible protein 2, a protein involved in the
deposition of neutral lipids into lipid droplets [82].
HIF1 also promotes the uptake of free fatty-acids
and the production of triacylglycerol in liver and adi-
pose tissue through the induction of the peroxisome
proliferator-activated receptor c [83]. Recently, it
emerged that HIF2 is responsible for the changes in
lipid metabolism observed upon loss of VHL in the
liver [84]. Liver-specific deletion of VHL in mice
resulted in steatosis accompanied by increased lipid
droplet formation and a reduction in the expression of
b-oxidation genes. The same study showed that HIF2a
also inhibits the expression of SREBP1c and its target
genes in the liver [84]. Interestingly, clear-cell renal car-
cinomas, which are characterized by loss of VHL and
stabilization of HIF1, also show frequent accumulation
of lipids [85]. While the exact role of lipid droplets in
supporting cancer-cell survival and

⁄ or tumour progres-

sion is not fully understood, it is possible that
enhanced storage of triacylglycerides could be benefi-
cial during conditions of intermittent hypoxia as they
may be used as a readily available fuel source after
reoxygenation.

Whole-body lipid metabolism and
cancer

Certain changes in lipid metabolism can contribute to
the predisposition of obese patients to cancer develop-
ment. Obesity is associated with an increased disease
risk for several cancer types. Current estimations are
that 20% of all tumours and 50% of endometrial and
oesophageal cancers can be attributed to obesity [86].
Obesity contributes to increased cancer risk mainly by
causing acquired insulin resistance. The accumulation
of lipids in muscle and liver lead to increased availabil-
ity of intracellular diacylglycerol and ceramide, which
impairs insulin signalling and inhibits insulin-induced
glucose uptake (reviewed in [87]). This leads to
increased secretion of insulin by pancreatic beta cells,
and enhances the availability of insulin-like growth
factor 1 (IGF1) through reduced production of insu-
lin-like growth factor-binding proteins 1 and 2 [88]
(Fig. 2A). Insulin and IGF1 are both pro-tumourigenic
growth factors that stimulate proliferation and can
protect cells from apoptosis (reviewed in [89]). In
addition, insulin resistance is also induced by chronic
low-grade inflammation [90]. Mouse models of diet-
induced or genetically induced obesity have shown that
the development of hepatocellular carcinoma is depen-
dent on the production of inflammatory cytokines [91].

In contrast, dietary restriction is thought to have an

anti-tumourigenic effect. However, the extent of this
may depend on the tissue of origin and the genetic
background of the cancer cells. A study has show that
human cancer-cell lines that display constitutive activa-
tion of the PI3K pathway are resistant to the growth-
inhibitory effects of dietary restriction in mouse xeno-
grafts [92]. Dietary restriction reduces the levels of cir-
culating insulin and IGF1 [93] and it is likely that

Fig. 2. Whole-body lipid metabolism and cancer. (A) Obesity and

insulin resistance can contribute to cancer development by increas-

ing the secretion of insulin by pancreatic b-cells and by enhancing

the availability of IGF1 as a result of the increased production of

IGF-binding proteins. Secretion of inflammatory cytokines by adi-

pose tissue can also promote transformation and proliferation of

tumour cells. (B) Tumour load promotes the breakdown of lipids in

the adipose tissue of cachexic patients. Tumour cells can use circu-

lating free fatty-acids as an energy supply, for membrane biosyn-

thesis or for signalling processes. Glycerol produced by the

breakdown of triacylglycerides can be used for gluconeogenesis in

the liver.

C. R. Santos and A. Schulze

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FEBS Journal 279 (2012) 2610–2623

ª 2012 The Authors Journal compilation ª 2012 FEBS

2615

constitutive activation of PI3K renders tumours inde-
pendent of their growth-promoting effect.

Alteration in lipid metabolism can also be a conse-

quence of cancer development as part of a disease
known as cancer cachexia (Fig. 2B). Cancer cachexia is
a wasting syndrome associated with extreme weight
loss and physical decline that is frequently observed in
cancer patients and leads to considerable morbidity.
Cachexia is characterized by loss of skeletal muscle,
with or without loss of adipose tissue, and can be asso-
ciated with anorexia, inflammation and insulin resis-
tance

[94].

Cachectic

patients

show

metabolic

alterations that include elevated carbohydrate utiliza-
tion, protein degradation and reduction in fat stores.
The reduction in fat stores is believed to be mainly
caused by increased lipolysis in adipose tissue, rather
than by a reduction in lipid biogenesis [95,96], and
leads to a reduction in adipocyte cell volume but not
of adipocyte cell number [97].

One of the mechanisms causing increased lipolysis in

patients with cachexia is the enhanced expression of
the

hormone-sensitive

lipase

in

adipocytes

[98].

Increased expression of the cell death-inducing DNA
fragmentation factor-alpha-like effector A has also
been observed in adipose tissue of cachectic patients
[99]. It attenuates glucose oxidation in vitro by block-
ing the entry of pyruvate into the mitochondria
through induction of PDK1 and PDK4 [99]. This pro-
motes the oxidation of fatty acids and could contribute
to the loss of adipose tissue. This inhibition of pyru-
vate dehydrogenase may explain why glucose adminis-
tration does not suppress fatty-acid oxidation in
cachectic patients [100].

While the mechanism that leads to increased lipoly-

sis in the adipose tissue of cancer patients has been
partially unravelled, the crucial link that dictates how
tumours induce these changes in adipocytes remains
elusive. However, the metabolic changes elicited during
cachexia can promote tumour growth by fuelling the
metabolism of cancer cells. Increased levels of circulat-
ing free fatty-acids, monoacylglycerides and diacylgly-
cerides have been observed in cachectic ovarian cancer
patients [101]. Glycerol molecules released during the
degradation of triacylglycerides can be used for gluco-
neogenesis by the liver, while free fatty-acids may
provide the tumour with energetic or biosynthetic sub-
strates or signalling molecules [102].

Lipid metabolism contributes to the
transformed phenotype of cancer cells

Owing to the diversity of their biological roles, lipids
contribute to several aspects of tumour biology, such as

growth, energy and redox homeostasis, as well as to the
dissemination of cancer cells to form distant metastases.
Some of the potential functions of altered lipid metabo-
lism in cancer cells are discussed below (see also Fig. 3).

Cell growth and proliferation

The high proliferation of cancer cells requires large
amounts of lipids as building blocks for biological
membranes. Lipid synthesis has been shown to be
required for cell growth, following treatment with
interleukin 3 or in response to activation of Akt in cul-
tured mammalian cells [7,57]. Interestingly, SREBP
function was also required for the maintenance of cell
size and organ size in D. melanogaster [57], indicating
that the importance of lipogenesis for growth is con-
served. SREBP activity is regulated during mitosis,
suggesting that the expression of lipogenic genes is
required for cell-cycle progression [103].

Overexpression of SCD, a target gene of SREBP,

has been observed in oncogene-transformed cells [104]
and in several human cancers [105,106]. SCD is associ-
ated with genetic predisposition to cancer in mice
[107], and is required for cell transformation in vitro
[108] and for the growth of prostate cancer cells in vivo
[106]. Stable silencing of SCD or disruption of the Scd
gene in mice, blocks lipid synthesis and increases b-oxi-
dation

through

activation

of

AMPK

[109,110].

Inhibition of SCD1 with a chemical inhibitor blocks
cell-cycle progression and induces cell death in lung-
cancer cells [111].

Fig. 3. Lipids can promote different aspects of cancer develop-

ment. Stimulation of fatty-acid synthesis by oncogenic signalling

and increased mobilization from adipose tissue as a consequence

of cachexia increase the availability of lipids in cancer cells. These

may contribute to several aspects of the tumour phenotype, such

as growth and proliferation, survival under oxidative and energy

stress, support of a high-glycolytic rate by promoting redox balance

and stimulation of signalling pathways that lead to proliferation and

invasion (see the text for more details).

Lipid metabolism in cancer

C. R. Santos and A. Schulze

2616

FEBS Journal 279 (2012) 2610–2623

ª 2012 The Authors Journal compilation ª 2012 FEBS

The importance of membrane synthesis in cancer

cells has been highlighted by the observation that the
expression and activity of choline kinase, an enzyme
required for the synthesis of phosphatidylcholine and
phosphatidylethanolamine (the major phospholipids
found in cellular membranes) is increased in tumours
from several tissues and correlates with poor prognosis
[112–114]. Choline kinase has oncogenic activity when
overexpressed, suggesting that the synthesis of phos-
pholipids is rate limiting for transformation [115,116].

Energy homeostasis

While there is compelling evidence for the requirement
of de novo lipid synthesis for cancer-cell proliferation,
it

remains

unexplained

why

this

enhanced

lipid

demand cannot be met by the uptake of lipids from
the bloodstream. Therefore, it is reasonable to hypoth-
esize that the process of lipid synthesis itself may con-
tribute to the tumourigenic phenotype. Cancer cells
use large amounts of glucose for energetic and biosyn-
thetic purposes [117], resulting in a high rate of lactate
production and secretion. This requires the activation
of mechanisms that equilibrate the intracellular pH
and can lead to the acidification of the tumour micro-
environment [118]. It is possible that one of the roles
played by lipid synthesis, at least in some cancer cells
and conditions, is as a carbon sink to sequester excess
pyruvate and avoid lactate production while still main-
taining a high glycolytic rate. Furthermore, it may also
contribute to redox balance. Hypoxia-tolerant organ-
isms use NADP

+

, produced during lipid synthesis, as

an electron acceptor when oxygen is not available
[119] and it has been proposed that hypoxic cancer
cells may follow a similar strategy [120]. Additionally,
in hypoxic cells, lipid synthesis-derived NADP

+

could

also help to increase the availability of cytoplasmic
NAD

+

required to maintain glycolysis. Ward &

Thompson [121] have recently proposed that a putative
mitochondria-cytosolic NADPH shuttle may exist, in
which cytosolic NADP

+

is used by isocitrate dehydro-

genase-1 to produce a-ketoglutarate. This metabolite
can then be transported to the mitochondria where
the recently described inverse reaction catalysed by
isocitrate dehydrogenase-2 [77–79] converts it back to
isocitrate with concomitant production of NADP

+

.

When oxygen is not available to maintain flux through
the electron transport chain, the ratio of mitochondrial
NADH

⁄ NAD

+

increases and therefore the excess

NADH could then be used by the mitochondrial nico-
tinamide nucleotide transhydrogenase [122] to transfer
a proton to NAPD

+

and generate NAD

+

that can be

made available to glycolysis through the malate-aspartate

or the glycerol phosphate shuttles. Lipid synthesis
would thus contribute both to redox balance between
the cytoplasm and the mitochondria and to maximize
glycolysis.

Resistance to oxidative stress

Recent evidence suggests that de novo lipid biosynthe-
sis in cancer cells can increase their resistance to oxida-
tive

stress.

Mammalian

cells

are

inefficient

at

synthesizing polyunsaturated fatty acids because they
lack an D3 desaturase. Consequently, a high rate of
de novo

lipid synthesis in tumours increases the relative

amount of saturated and monounsaturated fatty acids,
compared with those obtained through diet [123]. Poly-
unsaturated acyl-chains are more susceptible to peroxi-
dation. It has been shown that inhibition of lipid
synthesis renders cancer cells susceptible to cell death
induced by oxidative stress or chemotherapeutic agents
[123]. This intriguing observation requires further
investigation but suggests that inhibition of lipid syn-
thesis could be used to increase the effect of chemo-
therapy.

Resistance to energy stress

While most tumours exhibit a high rate of glucose
uptake, which contributes to support both their ener-
getic and biosynthetic requirements [124], some tumour
types exhibit increased dependence on lipid oxidation
as their main energy source. One such example is pros-
tate tumours, which generally display a low rate of
glucose utilization [125,126], show increased uptake of
fatty acids, such as palmitate [127], and overexpression
of some b-oxidation enzymes [128]. This may be
caused by the specialized metabolism of prostate epi-
thelial cells, which secrete large amounts of citrate into
the prostatic fluid. During transformation, prostate
cancer cells reactivate the TCA cycle and increase the
oxidation of citrate [129]. Moreover, it has also been
shown that b-oxidation is required for the proliferation
and survival of leukaemia cells [36].

Activation of b-oxidation may be crucial to support

cancer-cell viability during periods of energy stress.
Constitutive activation of the PI3K

⁄ Akt pathway sen-

sitizes haematopoietic cells to withdrawal of glucose or
growth factors [130]. However, activation of b-oxida-
tion is sufficient to maintain cell viability under these
conditions [38]. b-oxidation has also been shown to
contribute to ATP production and to resistance to oxi-
dative stress in glioblastoma cells, by providing sub-
strates

for

NAPDH

and

glutathione

production,

allowing cells to remove reactive oxygen species [37].

C. R. Santos and A. Schulze

Lipid metabolism in cancer

FEBS Journal 279 (2012) 2610–2623

ª 2012 The Authors Journal compilation ª 2012 FEBS

2617

Signalling functions of lipids

Increased fatty acid and cholesterol biosynthesis, as
well as the mobilization of free fatty-acids from triacyl-
glycerides, may lead to an increase in the levels of lip-
ids with a signalling function that can contribute to
different aspects of tumourigenesis.

Cholesterol is an important component of cholesterol-

rich microdomains, called lipid rafts, which coordinate
the activation of receptor-mediated signal-transduction
pathways [131]. In addition, an intermediate of choles-
terol synthesis, farnesyl-pyrophosphate, is required for
protein prenylation. Several proteins with important sig-
nalling functions are modified by the addition of an iso-
prenoid chain. Farnesylation is important for the activity
of Ras and Rheb proteins, while geranyl-geranylation is
required for Rho, Rac and cdc42 activity [132]. It has
been shown that inactivation of the retinoblastoma
tumour suppressor causes senescence by increasing the
prenylation of N-Ras through the E2 transcription fac-
tor-dependent activation of SREBP [61].

Lipids also form the structural basis of paracrine hor-

mones and growth factors, including prostaglandins,
leukotrienes, lyophosphatidic acid (LPA) or steroid hor-
mones. Prostaglandins and leukotrienes are derived
from the 20-carbon-unit arachidonic acid, produced
from phosphoglycerides by the action of phospholipases
A

2

and C. The synthesis of prostaglandin involves the

enzyme cyclooxygenase 2, which has been implicated in
inflammation and tumour

⁄ stroma interactions that pro-

mote tumour growth, neovascularization and metastatic
spread [133]. LPA is a water-soluble phospholipid com-
posed of glycerol, a single fatty-acid chain and a phos-
phate group. LPA stimulates cell proliferation, survival
and migration through the regulation of G-protein-cou-
pled receptors. Aberrant production of LPA can con-
tribute to cancer initiation and progression [134].

A recent study has shown that the modulation of

the levels of free fatty-acids can affect lipid hormone
synthesis. MAGL is overexpressed in aggressive can-
cer-cell lines and in advanced ovarian tumours, result-
ing in elevated levels of free fatty-acids, LPA and
prostaglandin.

Inhibition

of

MAGL

reduced

cell

migration, invasion and survival. However, the nega-
tive effect of MAGL inhibition on tumour growth
in vivo

was abolished when mice were kept on a high-

fat diet, suggesting that dietary lipids can affect
tumour-promoting signalling processes [135].

Concluding remarks

The last few decades of work have started to reveal
the importance of lipids for cancer biology. Novel

diagnostic techniques, such as acetate-based positron
emission tomography, are already providing new
insights into lipid metabolism in tumours, and inhibi-
tors of FASN are considered as promising anticancer
agents that have been shown to be effective in vitro
and in xenograft models [3]. However, the complex
interplay

between

oncogenic

signalling

and

lipid

metabolism, and the large spectrum of lipid functions
at both cellular and organismal levels, highlight the
importance of a more detailed understanding of the
alterations to lipid metabolism in cancer. Targeting
lipid metabolism may also offer novel therapeutic
strategies for cancer treatment.

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