Hindawi Publishing Corporation

BioMed Research International

Volume 2013, Article ID 824563, 10 pages
http://dx.doi.org/10.1155/2013/824563

Review Article
Mechanisms of Omega-3 Polyunsaturated Fatty Acids in
Prostate Cancer Prevention

Zhennan Gu,1,2 Janel Suburu,2 Haiqin Chen,1 and Yong Q. Chen1,2

1
State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University,
Wuxi 214122, China
2
Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem,
NC 27157, USA

Correspondence should be addressed to Yong Q. Chen; [email protected]

Received 6 March 2013; Revised 2 May 2013; Accepted 8 May 2013

Academic Editor: Gabriella Calviello

Copyright © 2013 Zhennan Gu et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This review focuses on several key areas where progress has been made recently to highlight the role of omega-3 polyunsaturated
fatty acid in prostate cancer prevention.

1. Introduction required enzymes and, therefore, PUFA must be obtained

from the diet. The n-6 and n-3 PUFA also cannot be intercon-
The health benefits of omega-3 polyunsaturated fatty acids verted in mammals, but within each series, their metabolism
(n-3 PUFA), mainly eicosapentaenoic acid (EPA 20:5) and can produce various lipids that differ in chain length and
docosahexaenoic acid (DHA, 22:6), have been long known. number of double bonds. Linoleic acid (LA, 18:2 n-6) is an n-6
Epidemiologic studies dating back to the 1970s were among PUFA found in high concentration in grains as well as many
the first to suggest that dietary PUFA may be beneficial seeds and meats. LA serves as a substrate to be converted
in preventing disease [1, 2]. Still today, studies continue to into a longer fatty acid, arachidonic acid (AA, 20:4 n-6), via
demonstrate the health benefits of n-3 PUFA; however, the a series of oxidative desaturation and elongation reactions.
mechanisms of action of n-3 PUFA are still not fully under- Of the n-3 fatty acids, alpha linolenic acid (ALA, 18:3 n-3)
stood. Many new discoveries have advanced our understand- is found at moderate levels in plants, seeds, leafy vegetables,
ing about the activities of n-3 PUFA against human disease. legumes, and nuts. ALA is not metabolized efficiently to
For example, DHA-receptor GPR120 has been demonstrated longer-chain n-3 PUFA, such as EPA and DHA.
to play a role in sensing and controlling obesity and metabolic Although they belong to two distinct families, n-3 and
syndrome [3]; the recently identified omega-3 mediators, n-6 PUFA are metabolized by some of the same enzymes,
resolvins, and protectins have been demonstrated to have specifically, delta-5-desaturase and delta-6-desaturase. Excess
anti-inflammatory and proresolving activities [4]. The pur- in one family of fatty acid can interfere with the metabolism of
pose of this review is to highlight the recent advances in the other and alter their overall biological effects [5]. During
our understanding of the mechanisms by which n-3 PUFA n-6 PUFA conversion, delta-6-desaturase, or fatty acid desat-
modulate prostate cancer development. urase 2 (FADS2), converts LA to gamma-linolenic acid (GLA,
18:3 n-6). This enzyme represents a rate-limiting step in the
2. Fatty Acids synthesis of AA from LA [6]. GLA is elongated to dihomo-
gamma-linolenic acid (DGLA, 20:3 n-6) through a chain
There are two major classes of PUFA: n-6 and n-3. Unlike reaction of four enzymes: a condensation reaction of the
saturated and monounsaturated fatty acid, PUFA cannot fatty acyl chain with malonyl-CoA, catalyzed by an enzyme
be synthesized de novo by mammals because they lack the encoded by the ELOVL5 gene (elongation of very long-chain
2 BioMed Research International

fatty acids, family member 5); a reduction reaction mediated a Swedish research group found that n-6 PUFA and n-6
by 3-ketoacyl-CoA reductase (KAR); a dehydration reaction PUFA precursors were significantly higher in malignant
catalyzed by 3-hydroxyacyl-CoA dehydratase (HACD); and tissues. This finding further demonstrates that n-6 dietary
a second reduction reaction catalyzed by trans-2,3-enoyl- fat is associated with prostate carcinogenesis [28]. In race-
CoA reductase (TECR). Finally, DGLA is converted to AA specific analyses based on a case-control study comprising
by delta-5 desaturase, or fatty acid desaturase 1 (FADS1) [6, 7]. 79 prostate cancer cases and 187 controls, Williams and
Interestingly, malonyl-CoA, which is necessary for fatty acid colleagues found that a high ratio of n-6 to n-3 fatty acids
elongation, is derived from the rate-limiting enzyme of the may increase the overall risk of prostate cancer among white
de novo fatty acid synthesis pathway, acetyl-CoA carboxylase. men and possibly increase the risk of high-grade prostate
Fatty acid synthesis is well described as an overactive pathway cancer among all men [29].
in many cancers [8–11], and its upregulation may also con- At the same time, epidemiological literature on the
tribute to the elongation of PUFA. association of n-3 PUFA and cancer, including correlational
In contrast to AA, the efficiency of ALA conversion to studies and migrational studies, suggest a protective role
DHA appears to be very low, below 5% in humans. Most played by n-3 PUFA. In a recent population-based prospec-
ingested ALA is subject to beta-oxidation to provide energy, tive cohort study of 90,296 Japanese subjects, Sawada et al.
and only a small fraction is converted to EPA [12, 13]. It reported that consumption of n-3-rich fish or n-3 PUFA,
was estimated that as low as 0.2% of ALA is converted to particularly EPA, DPA, and DHA, appears to protect against
EPA, 64% of EPA to docosapentaenoic acid (DPA, 22:5 n-3), the development of hepatocellular carcinoma (HCC) [32]. In
and 37% of DPA to DHA [14]. Thus, the overall amount another population-based prospective study in Japan, there
of DPA and DHA converted from ALA is about 0.13% was an inverse relationship between marine n-3 PUFA intake
and 0.05% of the starting ALA, respectively. These findings and the risk of colorectal cancer, but this association was
suggest that any contributions from the fatty acid synthesis only statistically significant in the proximal site of the large
pathway toward PUFA metabolism most likely favor n-6, bowel [33]. Chavarro et al. performed a nested case-control
rather than n-3, PUFA elongation. It is also very likely that study by analyzing blood samples of 14,916 healthy men and
synthesis of the longer n-3 fatty acids from ALA within the concluded that higher blood levels of long-chain n-3 fatty
body is competitively hindered by the n-6 analogues. It has acids were associated with a reduced risk of prostate cancer
been reported that the n-3 conversion efficiency is greater in [34]. Szymanski et al. conducted a meta-analysis of fish intake
women, possibly because of the importance of meeting the and prostate cancer by focusing on the incidence of prostate
DHA demands of the fetus and neonate [14]. cancer and prostate cancer-specific mortality. Their results
did not establish a protective association of fish consumption
with prostate cancer incidence but showed a significant 63%
3. PUFA and Cancer reduction in prostate cancer-specific mortality [35].
The results of correlational studies are mixed, some
Total fat intake and the ratio of n-6 to n-3 PUFA in the of them failing to demonstrate a statistically significant
Western diet have increased significantly since the Industrial effect. Several confounding factors could account for the
Revolution [15, 16]. Increased fat consumption has been asso- inconsistent results on the association between n-3 PUFA
ciated with the development of specific types of cancer such and prostate cancer. First, population-based studies mainly
as breast, colon, and pancreatic and prostate cancers, with the rely on data from self-reported dietary fatty acid intake or
notable exception of n-3 PUFA, which show protective effects from estimates based on national consumption, and these
against colon, breast, and prostate cancers in a number of assessments correlate poorly with direct measurements of
experimental systems [17–23]. Epidemiological studies about fatty acids in patient samples. In addition, the actual intake
the association of dietary fat and cancer suggests a protective in n-3 PUFA may be too low for a protective effect in some
effect of n-3 PUFA and a promoting effect of n-6 PUFA on cases. Second, the ratio of n-6 to n-3 fatty acids may be
cancer. Most clinical data regarding the effects of dietary fat more important than the absolute amount of n-3 PUFA,
on cancers are observational [24], and the results of such as suggested by animal and human studies [16, 36]. Using
studies are mixed, as many fail to demonstrate a significant a prostate-specific Pten knockout mouse prostate cancer
association between n-3 PUFA and reduced prostate cancer model, we showed that a ratio of n-6 to n-3 below 5 was
risk or tumor growth [20, 25–27]. effective in slowing cancer progression [3]. Brown et al.
The Western diet contains disproportionally high reported that AA might potentiate the risk of metastatic
amounts of n-6 PUFA and low amounts of n-3 PUFA, prostate cancer cell migration and seeding at the secondary
denoted as a high n-6 to n-3 PUFA ratio. Most data regarding site in vivo, and lowering the n-6/n-3 ratio in diet by uptake
the effects of high dietary n-6 PUFA are positively associated of n-3 PUFA might reduce this risk [37].
with prostate cancer incidence [28–30]. In a study of
Jamaican men undergoing prostate biopsy for elevated PSA
levels, a positive correlation was observed between n-6 fatty 4. Mechanisms of Action
acid LA and Gleason score and n-6 (LA) to n-3 (DHA)
ratio in erythrocyte membranes and prostate tumor volume 4.1. Integration of PUFAs into Plasma Membrane Glycerophos-
[31]. By comparing PUFA content from malignant and pholipids. Although fatty acids are consumed at high levels
benign prostatic tissues from the same prostate specimens, in a typical Western diet, tumor cells display a strong
BioMed Research International 3

dependence on de novo fatty acid synthesis [9, 10]. The opposing the action of PI3K [46, 47]. AKT can also be phos-
increased proliferation and metabolism of cancer cells could phorylated and activated by phosphoinositide-dependent
be the trigger for the abnormal requirement for fatty acid kinase-1 (PDPK1), a PH domain-containing kinase down-
compared to normal cells. Most newly synthesized fatty acids stream of PI3K (for review, see Franke, 2008) [48]. Hence,
are used to support membrane biogenesis in the form of intracellular PIP3 plays a pivotal role in this PI3K/PIP3 /AkT
glycerophospholipids, a class of lipids that are a major compo- cascade pathway.
nent of all cell membranes. Glycerophospholipids, including Using prostate-specific Pten knockout mice, an immune-
phosphatidylcholine (PC), phosphatidylserine (PS), phos- competent, orthotopic prostate cancer model, and diets with
phatidylethanolamine (PE), and phosphatidylinositol (PI), defined PUFA levels, we found that n-3 fatty acid reduced
contain a diglyceride, a phosphate group, and a simple prostate tumor growth, slowed histopathological progression,
organic molecule, such as choline or serine. and increased survival, whereas n-6 fatty acid had opposite
Dietary PUFA can influence the fatty acid composition effects. Introducing an n-3 desaturase, which converts n-6
of glycerophospholipids in cell membranes. In mammals, the to n-3 fatty acid, into the Pten knockout mice fed an n-6
sn-1 position on the glycerol backbone of glycerophospho- diet reduced tumor growth similarly to mice fed the n-3 diet.
lipids is usually linked to a saturated fatty acid such as stearic Tumors from mice on the n-3 diet had lower proportions of
acid (SA, 18:0), and the sn-2 position is linked to an n-6 PUFA, phosphorylated BAD and higher apoptotic indexes compared
such as AA. Feeding cells in culture, or animals, with n-3 with tumors from mice on the n-6 diet. These data suggest
PUFA can replace n-6 with n-3 fatty acid at the sn-2 position that n-3 PUFA can promote BAD-dependent apoptosis to
of glycerophospholipids; this is considered a diet-induced sn- modulate prostate cancer development [17]. We also found
2 fatty acid moiety change [17, 38, 39]. We have analyzed the that PUFAs modify glycerophospholipid content. DHA can
incorporation efficiency of PUFAs into glycerophospholipids replace the fatty acid at the sn-2 position of the glycerol
in prostate cancer cells. Approximately 25% of input albumin- backbone, thereby changing the species of phospholipid.
conjugated fatty acids were incorporated into cells within 48 DHA also inhibited AKTT308 but not AKTS473 phosphoryla-
hours. The majority of these newly integrated PUFAs were in tion, altered PIP3 and phospho-AKTS473 protein localization,
the form of PC and PE [40]. These data clearly suggest that decreased pPDPK1S241 -AKT and AKT-BAD interaction, and
the fatty acid at the sn-2 position of glycerophospholipids is suppressed prostate tumor growth. Knockdown of BAD
influenced by cellular PUFA uptake. eliminated n-3 PUFA-induced cell death, and reintroduction
n-3 PUFA influences cell membrane conformation and of BAD restored the sensitivity to n-3 fatty acids in vitro.
signaling dynamics. The greater density of n-3 PUFA, com- Knockout of BAD diminished the suppressive effect of n-3
pared to n-6 PUFA, dictates their aggregation near the lipid- PUFA on prostate tumor growth in vivo. These data suggest
water interface. This characteristic can significantly affect that modulation of prostate cancer development by PUFA is
plasma membrane properties, including membrane fluidity, mediated in part through the PI3K/AKT survival pathway
phase behavior, and permeability [41]. These membrane per- [17, 40].
turbations can bring about changes associated with receptor Hu et al. reported that n-3 PUFA-induced apoptosis in
activation, such as diffusional coupling of various peripheral human prostate cancer cells occurs through upregulation
proteins required in G protein-coupled receptor signaling of syndecan-1 (SDC-1) expression followed by concomitant
(GPCR) [42, 43]. Additionally, because of its high level of suppression of PDPK1/AKT/BAD phosphorylation [49]. n-
unsaturation, DHA has very poor affinity for cholesterol, 3 fatty acids may also decrease cell proliferation and induce
which is enriched in lipid rafts of the cell membrane. Lipid apoptotic cell death in human cancer cells by decreasing
rafts are important membrane domains for cell signaling as signal transduction through the AKT/NF𝜅B cell survival
many receptors and proteins are enriched in this domain, pathway and by modulating the PI3K/AKT/p38 MAPK
such as epidermal growth factor receptor (EGFR) [44]. pathway [50, 51].
Hence, incorporation of n-3 PUFA into membrane lipids
can disturb the formation of lipid rafts and suppress raft-
associated cell signal transduction [13, 44]. 4.2. PUFA Mediator. A common fate of unsaturated lipids
The serine/threonine protein kinase AKT (protein kinase released from the membrane is oxidation. AA is the precursor
B) is activated in many solid tumors and hematological of highly bioactive lipid mediators metabolized by a number
malignancies. AKT acts downstream of phosphatidylinositol of enzymes belonging to the cyclooxygenase (COX) and
3-kinase (PI3K) signaling and is a key regulator of multiple lipoxygenase (LOX) families, as well as cytochrome P450.
survival pathways. AKT is known to phosphorylate and COXs have two well-characterized isoforms, COX1 and
inactivate the proapoptotic Bcl-2 family member BAD as one COX2. COX1 is a constitutively expressed gene in most
of its prosurvival tactics [45]. Phosphatidylinositol (PI) is a tissues, whereas COX2 is an immediate-early response gene,
negatively charged constituent of lipid membranes. Specific which is strongly induced in many human malignancies [52].
kinases phosphorylate the hydroxyl groups on positions 3󸀠 , Signal transduction of n-6 PUFA-derived lipids and the effect
4󸀠 , or 5󸀠 of the inositol ring, and PI3K primarily gener- of these lipid mediators on the organism have been well
ates PI-3,4,5-trisphosphate (PIP3 ) from PI-4,5-bisphosphate characterized. For example, AA-derived lipid mediators are
(PI(4,5)P2 ). PIP3 acts as a second messenger to activate pleck- associated with a variety of activities, including inflammation
strin homology (PH) domain-containing proteins, including and cancer. Evidence from human studies also supports the
AKT. Conversely, PIP3 is hydrolyzed to PI(4,5)P2 by PTEN, important role of COXs and LOXs in PUFA metabolism and
4 BioMed Research International

cancer [53–56]. Because of its high expression in inflamma- both Lox12 and Lox15 metabolites are not critical for prostate
tion and cancer, COX2 has been the subject of intense study cancer growth in this model (Chen et al., unpublished).
and proposed as a target for cancer therapy [57–59].
In contrast to n-6 PUFA, the metabolism of n-3 PUFA
is not well understood. Interest in n-3 PUFA-derived lipid 4.3. Fatty Acids Receptors. Lipids are ligands for cell-sur-
mediators began with observations of Greenland Eskimos face G protein-coupled receptors (GPCRs), toll-like recep-
whose diet is rich in marine-derived fish and showed lower tors (TLRs), and peroxisome proliferator-activated receptors
mortality from coronary heart disease and lower preva- (PPARs). G protein-coupled receptors (GPCRs) are impor-
lence of inflammation-related diseases, such as psoriasis, tant signaling molecules for many aspects of cellular function.
inflammatory bowel disease, asthma, rheumatoid arthritis, They are members of a large family that share common
and other autoimmune diseases [60, 61]. Serhan et al. structural motifs, such as seven transmembrane helices and
reported that inflammatory exudates in the murine air pouch the ability to activate heterotrimeric G proteins. Recently,
from mice treated with n-3 PUFA and aspirin contained a several groups reported that unbound free fatty acids can
series of bioactive compounds. Using an unbiased lipidomics activate GPCRs, including GPR40, GPR41, GPR43, GPR84,
approach, they identified and named the EPA-derived E- and GPR120 [3]. Short-chain fatty acids are specific ligands
resolvins (RvE1 and RvE2), DHA-derived D-resolvins (RvD1 for GPR41 and GPR43, medium-chain fatty acids for GPR84,
and RvD2), and (neuro-)protectin (PD1) [62]. and long-chain fatty acids for GPR40 and GPR120 [70–73].
RvE1 and RvE2 are protective in a wide variety of disease Activation of GPR84 receptor by medium-chain fatty acids
models, mainly through their anti-inflammatory activities. triggered the production of the proinflammatory cytokines
RvE1 can resolve inflammation caused by bacterial infection from leukocytes and macrophages. The function of GPR84
of periodontal disease in a rabbit model [63], prevent neo- may be associated with chronic low-grade inflammation-
vascularization after oxygen-induced retinopathy [64], and associated disease [74].
suppress neutrophil infiltration in an acute peritonitis model GPR40 and GPR120 have been reported to be activated
[65]. RvD1, RvD2, and PD1 also have protective activities by long-chain fatty acids such as DHA, EPA, and AA [73, 75].
in a variety of animal models, including models of lung As a G protein-coupled receptor, GPR40 can activate the
injury, insulin resistance, peritonitis, wound healing, and phospholipase C and phosphatidylinositol signaling path-
atherosclerosis [66]. RvD1 was shown to reduce leukocyte ways [76]. Although GPR40 is preferentially expressed in
infiltration in murine inflammatory exudates [67] and RvD2 pancreatic 𝛽-cells and is known to mediate insulin secretion
was shown to reverse inflammatory pain in mice [68]. PD1 [77], several groups showed that it is expressed in the
has been reported to regulate amyloid beta secretion and brain where it mediates the antinociceptive activity of DHA
thereby improve neuronal survival in a mouse model of [78, 79]. Recently, Oh and others reported that GPR120
Alzheimer’s disease [69]. Although ample data indicate that functions as an n-3 PUFA receptor in vitro and in vivo [3]
these n-3 PUFA-derived mediators can resolve inflammation, and suggested that diminished activation of GPR120 can be
little is known about their role in inflammation-related an important contributor to obesity, insulin resistance, and
cancers, such as prostate and colon cancers. tissue inflammation [80, 81]. GPR120 is highly expressed
Due to the existence of multiple oxygenases, the role in adipose tissue, proinflammatory bone marrow-derived
of each enzyme in the development of prostate cancer has CD11C+ macrophages (BMDCs), mature adipocytes, and
not been studied systematically in a single system or animal monocytic RAW 264.7 macrophage cells. DHA strongly
model. Furthermore, studies performed in animals rarely inhibited LPS-induced phosphorylation of JNK and IKK𝛽,
take diet into account. To systematically assess the interaction I𝜅B degradation, cytokine secretion- and inflammatory gene
between oxygenases and dietary PUFA in a single animal expression level in GPR120-positive cells. These effects of
model of prostate cancer, we knocked out Cox1, Cox2, DHA were completely prevented by GPR120 knockdown,
Lox5, Lox12, or Lox15 in prostate-specific Pten null mice. demonstrating that these anti-inflammatory effects were
specifically exerted through GPR120. An n-3 PUFA diet
Our preliminary results indicate that tumor growth was
containing 27% fish oil led to improved insulin sensitivity
significantly increased in Cox1−/− Pten null mice on n-3 diet with increased glucose infusion rates, enhanced muscle
compared to Cox1-wild-type Pten null littermates. This result insulin sensitivity, and greater hepatic insulin sensitivity.
suggests that Cox1 is required for the protective effects of The n-3 PUFA diet had no effect in the GPR120 knockout
n-3 PUFA. Interestingly, tumor growth was decreased in n-6 (KO) mice. On chow diets, the GPR120 KO mice showed
PUFA fed Cox1−/− Pten-null mice compared to n-6 fed Cox1- moderate insulin resistance with no changes in food intake or
wildtype Pten-null mice, suggesting that n-6 metabolites of body weight. On high-fat diet (HFD), the GPR120 KO mice
Cox1 promote tumor growth. Loss of Cox2 reduced prostate gained more weight than wild-type controls [3]. In humans,
tumor growth on both n-3 and n-6 diets, suggesting that GPR120 expression in adipose tissue is significantly higher in
the suppressive effect of n-3 PUFA is independent of Cox2 obese individuals than in lean controls [80]. Ichimura and
metabolism. Loss of Lox5 reduced prostate tumor growth colleagues compared sequences of GPR120 exons in obese
on n-6 diet but had no effect on n-3 diet; loss of Lox12 or populations and discovered a deleterious nonsynonymous
Lox15 did not affect prostate tumor growth on either diet. mutation (R270H) [80]. Their population study showed that
These results suggest that the promotion of prostate tumor the GPR120R270H variant correlated with obesity. Further
growth by n-6 diet is dependent on Lox-5 metabolism and investigation in vitro demonstrated that the GPR120R270H
BioMed Research International 5

variant was unable to respond to long-chain fatty acid reduction in tumor growth as a result of dietary n-3 PUFA
stimulation. This inactive mutant of GPR120 may contribute is accompanied by an increase in the expression of secreted
to its significant association with obesity [80]. SDC-1 [49, 101].
Toll-like receptors (TLRs) are transmembrane glycopro- Several other receptors have been suggested as targets for
tein receptors that are important regulators of the innate n-3 PUFA action. Turk et al. reported that DHA can induce
immune system. TLRs are considered a link between innate the alteration in both the lateral and subcellular localization
(nonspecific) and adaptive (specific) immunity and con- of EGFR and suppress EGFR signaling, which suggests
tribute to the immune system’s capacity to efficiently combat implications for the molecular basis of cancer prevention by
pathogens [82]. TLR expression is increased in tumors, DHA [44, 102]. It is also reported that DHA can increase
including breast, colorectal, melanoma, lung, prostate, pan- CD95 (Fas ligand death receptor) cell surface expression
creatic, and liver cancer [83]. Activation of TLRs triggers and may mediate CD95-induced apoptosis [103]. For more
a signaling cascade producing inflammatory cytokines that information about PUFA receptor interaction, please refer to
recruit components of the adaptive immune system to kill the a review by Lee et al. [104].
pathogen [84]. Among the family of TLRs, TLR4 and TLR9
have been reported to be associated with prostate cancer
[85–87]. Panigrahy et al. reported that saturated fatty acids 4.4. Other Mechanisms. Nuclear factor erythroid-2-related
activated, and DHA inhibited, TLR2- and TLR4-mediated factor 2 (Nrf2) is a basic leucine zipper transcription factor.
proinflammatory activity in a cell culture system [88]. Satu- Nrf2 is sequestered in the cytoplasm by Kelch-like ECH-
rated fatty acids may stimulate the TLR4 signaling pathway to associated protein 1 (Keap1) under basal conditions. When
trigger the production of proinflammatory mediators, which the cell is challenged by oxidative stress, Nrf2 is released from
may contribute to neuronal death [89]. Keap1 inhibition, translocates to the nucleus, forms a com-
PPARs (PPAR𝛼, PPAR𝛽/𝛿, and PPAR𝛾) are a super- plex with other factors, and activates transcription of genes
family of ligand-activated transcription factors and nuclear containing an antioxidant response element (ARE) in their
hormone receptors. The syndecan family of cell surface promoter region. Nrf2 has been reported to play an important
proteoglycans share a structure of small, conserved cyto- role in lung injury reversal, human endothelial cell survival,
plasmic and transmembrane domains and larger, distinct neuroinflammation, hyperoxia, lung damage from cigarette
ectodomain. They are implicated in a variety of physiologic smoking, and impaired function of macrophages [105]. Other
and pathologic processes such as nutrient metabolism, energy studies suggest that Nrf2 suppresses inflammation by inhibit-
homeostasis, inflammation, and cancer. Growing evidence ing NF𝜅B activation through regulation of redox balance,
has demonstrated that PPAR𝛾 serves as a tumor suppressor calcium signaling, and PPARs [106]. Various human cancers,
in cancer (see review of Robbins and Nie, 2012) [90]. n-3 such as lung cancer, frequently exhibit increased levels of
PUFA can induce apoptosis in human prostate cancer cells Nrf2 [107]. Downregulation of nuclear Nrf2 gene expression
by activating the nuclear receptor PPAR𝛾 and upregulating by RNAi-mediated silencing in nonsmall cell lung cancer
the PPAR𝛾 target gene, syndecan-1 (SDC-1) [49, 91]. It has inhibits tumor growth and increases efficacy of chemotherapy
been suggested that n-3 PUFA induces cell apoptosis in [108]. Cancer cells are suspected to hijack the Keap1-Nrf2
prostate cancer via a mechanism of LOX15-mediated SDC- system as a means to acquire malignant properties. Indeed,
1-dependent suppression of PDPK1/AKT/BAD phosphory- the prognosis of patients carrying Nrf2-positve cancers is
lation [49, 91]. SDC-1 upregulation by DHA has also been poor [105]. Oxidized n-3 fatty acids can react directly with the
demonstrated in human breast cancer cells [19, 92–94] and in negative regulator of Nrf2, Keap1, by dissociating them and
n-3 PUFA-enriched mammary glands and liver of fat-1 mice inducing Nrf2-directed gene expression [109]. For example,
[95]. n-3 PUFA mediators can activate Nrf2 in vascular endothelial
SDC-1 plays several important cellular functions. It reg- cells to prevent oxidative stress-induced cytotoxicity [110].
ulates many steps of leukocyte recruitment in noninfectious DHA and EPA can induce Nrf2 expression and suppress
inflammatory diseases, attenuates inflammation by modu- lipopolysaccharide-(LPS-) induced inflammation [111]. Evi-
lating heparin sulfate-binding proinflammatory factors, and dence of Nrf2-mediated response modulated by n-3 PUFA
plays a key role in the normal remodeling of injured cardiac in prostate cancer came from a randomized clinical trial.
tissues [96]. Loss of cell surface SDC-1, seen in many Eighty-four men with low-risk prostate cancer were stratified
carcinomas such as skin cancer and colorectal adenocar- based on self-reported dietary consumption of fish oil.
cinomas, favors acquisition of the metastatic phenotype in Exploratory pathway analyses of rank-ordered genes revealed
cancer cells [97]. There is very limited information about the modulation of Nrf2 or Nrf2-mediated oxidative response
SDC-1 expression in prostate cancer. Some studies reported after 3 months of fish oil supplementation (𝑃 = 0.01) [112].
an inverse relationship between SDC-1 and Gleason score Calcium (Ca2+ ) signaling is a ubiquitous mechanism in
[98, 99], but a tissue microarray analysis in another study the control of cell function. The transient receptor potential
showed an increase in SDC-1 with tumor progression [100]. channels (TRP channels) are 6 transmembrane-spanning
Our own studies have shown reduced expression of SDC- proteins with both amino and carboxyl tails located on
1 in prostate cancer cell lines compared to normal prostate the intracellular side of the membrane. Ca2+ flux through
epithelial cells and lower expression in androgen-dependent TRP channels located in the plasma membrane and in the
LNCaP cells compared to androgen-independent PC3 and membranes of excitable intracellular organelles can promote
DU145 cells [49]. In a mouse prostate cancer model, the changes in intracellular free Ca2+ concentrations and the
6 BioMed Research International

Table 1: Mechanism of n-3 PUFA action.

Target Mechanism of action References
Membrane PIPs Suppress PI3K/AKT/BAD survival pathway [17, 40]
SDC-1 Suppress PI3K/AKT/BAD and AKT/NF𝜅B survival pathway [49]
Unknown Suppress AKT/NF𝜅B or PI3K/AKT/p38 MAPK pathway [50, 51]
GPR40 Mediate insulin secretion, cell proliferation [75–77]
GPR120 Anti-inflammation [3, 80]
TLRs Suppress the production of proinflammatory mediators [88, 89]
PPARg Induce cell apoptosis [90]
Nrf2 Suppress inflammation, reduce oxidative stress [106, 109, 110]
Calcium signaling Inhibit cell proliferation [114]
COXs Promote inflammation [52]
LOXs Promote inflammation [53]
E-resolvins Resolve inflammation [62]
D-resolvins Resolve inflammation [62]

membrane potential, which can modulate the driving force metabolic processes, including 𝛽-oxidation, lipid release
for other ions and Ca2+ itself [113]. Evidence suggests that from glycerophospholipids, cellular signaling of membrane
TRP channel function can be modulated both directly and bound proteins, eicosanoid synthesis, and direct activation
indirectly by n-3 fatty acids [114]. It was demonstrated that of nuclear receptors and gene transcription, all of which
DHA and EPA at physiological concentrations have the ability may influence the development and progression of prostate
to evoke small currents, which seems to be dependent on cancer. Overall, there seems to be an exceptionally broad
the previous sensitization of the channel by protein kinase potential for the mechanisms mediating cancer prevention
C (PKC). Whether these effects are due to the action of by n-3 PUFA (summarized in Table 1). We expect that new
these PUFAs on the agonist binding site or are due to research in lipidomics and metabolomics will provide new
conformational changes caused by TRP protein interactions techniques and approaches to answering the many questions
with the lipid bilayer requires further investigation [115]. that remain regarding the mechanisms underlying the health
Recent findings also indicate that TRP channel function benefits of n-3 PUFA.
can be modulated by D and E resolvins. Resolvin binding
on GPCRs seems to be part of the mechanism underlying
the resolvin-mediated regulation of TRP channel function
[116]. DHA significantly reduces oxidative stress-induced Abbreviations
endothelial cell Ca2+ influx. This effect might be associated, PUFA: Polyunsaturated fatty acid
at least in part, with altered lipid composition in membrane EPA: Eicosapentaenoic acid (20:5, n-3)
caveolar rafts [117]. Ca2+ has been shown to be essential DHA: Docosahexaenoic acid (22:6, n-3)
for increased cell proliferation in prostate cells [118]. Sun LA: Linoleic acid (18:2, n-6)
et al. observed significantly higher Ca2+ influx in prostate AA: Arachidonic acid (20:4, n-6)
cancer cells. They reported that high ratio of Ca2+ /Mg2+ ALA: Alpha linolenic acid (18:3, n-3)
facilitated Ca2+ influx and led to a significant increase in FADS: Fatty acid desaturase
cell proliferation of prostate cancer [119]. Thus, one could GLA: Gamma-linolenic acid (18:3, n-6)
speculate that n-3 PUFA might indirectly modulate prostate DGLA: Dihomo-gamma-linolenic acid (20:3, n-6)
cancer growth by directly modulating Ca2+ influx. KAR: 3-Ketoacyl-CoA reductase
HACD: 3-Hydroxyacyl-CoA dehydratase
TECR: Trans-2,3-enoyl-CoA reductase
5. Conclusions DPA: Docosapentaenoic acid (22:5, n-3)
PC: Phosphatidylcholine
Cancer incidence and mortality are high in the Western world PS: Phosphatidylserine
and a high n-6 to n-3 PUFA ratio in the Western diet may PE: Phosphatidylethanolamine
be a contributing factor. There is much evidence to suggest PI: Phosphatidylinositol
that n-3 PUFA has antiproliferative effects in cancer cell SA: Stearic acid (18:0)
lines, animal models, and humans. Direct effects on cancer GPCR: G Protein-coupled receptor
cells and indirect effects on the host immune system (anti- EGFR: Epidermal growth factor receptor
inflammation) likely contribute to the inhibitory effect of n-3 AKT: Serine/threonine protein kinase (protein kinase B)
fatty acids on tumor growth; however, further investigation PI3K: Phosphatidylinositol-3-kinase
is warranted. n-3 PUFA may also regulate other complex PIP3 : PI-3,4,5-trisphosphate
BioMed Research International 7

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