12

Selenoproteins and Thyroid Cancer

Leonidas H. Duntas 1

, Peter P.A. Smyth 2

1

Endocrine Unit, Evgenidion Hospital, University of Athens, Greece

E-mail: ledunt@otenet.gr

2

UCD School of Medicine and Medical Science, University College, Dublin,

Ireland

Selenoproteins, in which Se exists in the form of selenocysteine, are essential for

protection against oxidative damage and cancer. Genetic data has provided

evidence that reduced levels of these proteins, induced by loss of heterozygosity

or chromosomal alterations [1]

, result in cellular oxidative stress as well as

derangement of signaling cascades leading to inflammation, malignancy and

progression. While several tumor species have been shown to be vulnerable,

because of its high Se content and rich selenoprotein network, the thyroid is

especially exposed to risk when intrathyroid Se content is low and Se intake is not

appropriate. However, there is as yet insufficient evidence on whether Se

supplementation via Se compounds and/or via fortification of food, achieves

reduction in the risk of cancer, and more specifically that of thyroid cancer and

whether Se is able of reducing aggression and tumor progression and whether

increased availability of Se and its compounds is capable of lowering anticancer

drug toxicity and drug resistance.

12.1� Introduction

Selenium (Se) is a dietary trace element unique in that it is co-translationally

inserted in the form of the 21st amino acid, selenocysteine (Sec), into

selenoproteins, the insertion process, characterized by great complexity, being

specified by selenium’s own codon in mRNA [2]

.

The human selenoproteome consists of 25 selenoproteins which are essential

J. Liu et al. , Selenoproteins and Mimics© Zhejiang University Press, Hangzhou and Springer-Verlag Berlin Heidelberg 2011

(eds.)

12� Selenoproteins and Thyroid Cancer 174

for life. Thus, selenium’s capacity to modify their expression through its wide

array of functions plays a primary role in the maintenance of human health. The

main groups of selenoproteins are glutathione peroxidases (GPxs), iodothyronine

deiodinases (D1-4), thioredoxin reductases (TrxRs) and selenoprotein P (SeP), all

of which exert actions as antioxidants, modify redox status, influence the immune

function and regulate thyroid hormone metabolism [3]

.

Among various biological roles attributed to Se are the trace element’s

function as an antioxidant that detoxifies reactive oxygen species (ROS) and

combats oxidative stress via GPxs, TrxRs and SeP [4]

. ROS are products of cellular

oxygen metabolism, whose excess leads to oxidative stress, thereby causing DNA-

damage and cell death [4]

. Geographic location and dietary factors are thought to

play a part in susceptibility: populations living in selenopenic areas and

individuals with low Se intake are prone to increased oxidative stress, this

possibly contributing to increased cancer risk.

Selenium and cancer have a complex relationship. As noted above,

epidemiologic studies indicate that the risk of several types of cancer is increased

in selenopenic areas, while several confounding factors, such as the duration of Se

deficiency and the presence of other chronic diseases, may also be involved [5]

.

Plasma Se levels reflect the concentration of circulating selenoproteins and

consequently long-standing Se deficiency predisposes the subject to immune

dysfunction and disease. Se has therefore been endorsed as a chemopreventive

agent, with large studies that mainly focus on prostate cancer underlining this

potential [6]

. It is important, however, to emphasize that in the administration of Se

as a chemopreventive agent, the precise chemical forms and dose must be taken

into account in order to determine the parameters of its anti-tumor effects [7]

.

Accordingly, Se supplementation should preferably be performed via compounds

in which the Se moiety is methylated, such as selenomethionine, since they exhibit

the most potent chemopreventive actions while producing less toxic effects [8]

.

The aim of this review article is to appraise the current knowledge regarding

the relation of selenium and cancer, and in particular the role of Se in the

pathogenesis of thyroid cancer, and to briefly describe potential chemopreventive

and chemotherapeutics interventions.

12.2� Selenoproteins, Chemoprevention and Cancer

Several studies have found an inverse correlation of Se status and cancer. The

most compelling data showing efficacy of Se administration as an anti-cancer

preventive agent has been provided by the Nutritional Prevention of Cancer (NPC)

trial [9]

. In this milestone study in cancer chemoprevention, 1,312 patients with

non-melanoma skin cancer were randomly assigned to placebo or Se 200 μg/d

(Se-enriched yeast) for a period of 4 – 5 years and 5 – 6 years of follow-up. At the

completion of the treatment period, subjects with prostate, lung and colon

12.2� Selenoproteins, Chemoprevention and Cancer� 175

carcinomas receiving Se showed 50% lower cancer mortality and 37% lower total

cancer incidence , while a further protective effect on prostate cancer, though not

on lung and colon cancer, was detected at the end of the follow-up [9,�10]

.

A recent meta-analysis, including several highly indicative studies from China,

assessing the effect on the prevention of gastrointestinal tumors of antioxidants

administration concluded that Se supplementation, in contrast to other antioxidants,

has a favorable effect, reducing by 50% the risk of hepatocellular carcinoma [11]

.

In the Chinese province of Qidong, where hepatitis B and severe selenium

deficiency are endemic, administration of 30 – 50 μg of sodium selenite led to a

50% fall in cases of liver cancer [12,�13]

. Meanwhile, in the province of Linxian,

with the highest esophageal cancer prevalence worldwide, selenium supple–

mentation with vitamin E and β-carotene produced a 13% decrease in total cancer

incidence [14]

.

Τhe SELECT study is the largest human prevention trial ever undertaken to

determine whether Se or vitamin E,�or both, can prevent prostate cancer and

disease in healthy men [15]

. In this randomized, double-blind, placebo-controlled

trial, 35,313 relatively healthy men aged 50 years or older received L-

selenomethionine 200�μg/d or/and alpha-tocopheryl acetate 400 IU/d for 3 years.

The results did not reveal any preventive effect of Se or vitamin E alone, or

combined, on prostate or any other cancer. However, a comparison of the results

with those of other studies appears to indicate that the relatively high Se levels at

the baseline may be responsible for this outcome [16]

. Overall, as was also seen in

the NPC trial, the strongest effect was documented in subjects with the lowest

plasma Se levels, this pointing to a negative correlation between plasma Se status

and outcome of treatment. Moreover, in the same trial in a subgroup analysis,

subjects at the highest tertile of Se baseline, above 121 μg/L, who were

supplemented with Se-enriched yeast, presented a statistically significant increase

in total cancer incidence [15,�17]

. However, this analysis questions the use of Se

supplementation in subjects with high-normal Se plasma levels and draws

attention to the necessity of determining the Se level on an individual basis when

supplementation is implemented.

Nevertheless, it is of importance to underline that monomethylated Se

compounds have been proved effective in vitro at low concentrations for

chemoprevention. Selenomethylcysteine forms a reservoir which provides a

steady supply of monomethylated Se, maintaining it at a high level, thus inhibiting

the cell growth of the transformed cell [7,�18]

.

In contrast to the USA study, a recent case-control study in Europe, where

extensive selenopenia has been documented, demonstrated a clear-cut inverse

correlation of bladder cancer risk and serum Se levels [19]

.

Hence, despite some discrepancies, there is ample evidence from prospective

studies suggesting a protective role of Se with regard to lung, esophageal, gastric

and, most particularly, to prostate cancer. These various studies as well as the

molecular pathways that may be involved in the anti-cancer effect of Se have been

discussed at length in a recent review by Rayman MP [17]

.

In experimental studies, Se has been reported to prevent cancer when

12� Selenoproteins and Thyroid Cancer 176

animals received amounts of Se higher than their nutritional needs [20,� 21]

.

Although the precise mechanism and action of the various selenoproteins have

not as yet been fully elucidated, GPxs and TrxRs, the major redox systems of

the cell, appeared to be the most heavily involved in cancer development and

chemoprevention (Tables 12.1a and 12.1b). Recently, associations of GPx1

polymorphisms and lung cancer and between young-onset prostate cancer and

polyalanine polymorphism in exon1 of GPx1 have been reported [22,� 23]

.

Concomitantly, the fact that other studies revealed high levels of Sel15 in human

and mouse prostate strongly indicated that tumor growth and apoptosis of

mesothelioma are dependent upon the Sel15 genotype, thus clearly suggesting

implication of this selenoprotein in carcino-genesis [24]

. The existing data

therefore indicate an important role of seleno-proteins in cancer development

and support the notion that decreased Se levels result in decreased selenoprotein

activity and increased cancer risk. Se supple-mentation may reverse the reduced

levels of selenoproteins; however, it is not as yet clear whether the higher Se

requirements in cases with GPx1 and Sel15 polymorphisms may lead to the

achievement of baseline selenoprotein levels.

Table 12.1a� Selenocysteine-containing Proteins (I)

Enzyme/Protein Abbreviation

Tissue, Cellular

Distribution

Functions

Glutathione peroxidases GPx

Cytosolic cGPx (GPx1)

Cytosolic, tissues and

cells

Gastro-intestinal GPx (GPx2) GI-tract, cytosolic

Plasma or extracellular pGPx (GPx3)

Plasma, kidney, GI tract,

thyrocytes

Phospholipid-

hydroperoxide

PHGPx (GPx4)

Testes, cytosolic and

membranes, various splice

forms, many tissues and

cells

Glutathione peroxidase (GPx6)

Embryos and olfactory

epithelium

Antioxidant,

catalyzing redοx-

reactions

Polymerization of Tg

Protection of

biomembranes, sperm

fertilization

Olfaction

Deiodinases

Type I 5′DI

Liver, kidney, thyroid and

in many other tissues

Type II 5′DII

Brain, hypothyroid

pituitary, placenta, brown

adipose tissue

Type III 5′DIII

Brain, uterus, placenta,

embryonic brain and liver

Deiodination of

T4 to T3

Deiodination of T4 and

T3 to rT3 and T2

12.3� Selenoproteins: Modes of Action and Thyroid Cancer� 177

Table 12.1b� Selenocysteine-containing Proteins (II)

Enzyme/Protein Abbreviation

Tissue, Cellular

Distribution

Functions

Thioredoxin reductases TrxR

Thioredoxin reductase 1 TrxR1

Liver, kidney, heart, bone,

cytosolic

Thioredoxin reductase 2 TrxR2 Mitochondrial, testes

Thioredoxin reductase 3 TrxR3

Liver, kidney, heart,

mitochondrial

Antioxidant, catalyzing

redοx-reaction

Antioxidant, catalyzing

redοx-reaction

Selenoprotein P SeP Liver, many tissues Plasma Se carrier

Selenoprotein 15 Sel15 Brain, lung, testes, liver

Tumor suppression

function

Selenoprotein W SelW

Many tissues, gender

specific expression

Stress response

Selenoprotein S SelS Endoplasmic reticulum

Modulation of

inflammatory signaling

Selenoprotein M SelM Brain, thyroid, heart, lung,

Brain protection? (low

levels in Alzheimer’s

disease)

Trxs, essential enzymes in cell differentiation and growth, also have a central

role in Se’s anti-oxidative stress action. Recently, it has been reported that

administration of sodium selenite in a number of lung cancer cell lines was shown

to be more effective than conventional cytotoxic drugs [25]

. Inhibition of TrxR1—

which is up-regulated in several tumors—induced by sodium selenite led to

increased expression of various transcript forms of Trx1 mRNA, impairment in

Trx1 protein synthesis and enhanced toxicity of sodium selenite [25]

.

Another important mediator of Se’s actions is SeP which, possessing a dual

role as antioxidant and Se transporter, most likely plays a determinant role in the

anti-carcinogen actions of Se. A recent study investigated the effects of

polymorphisms in the SeP-1 gene, Se supplementation and disease status on the

SeP plasma isoforms [26]

. There was a reduction in the functional 60�kDa isoform

of SeP in plasma, which was reversed following Se substitution, this possibly

potentiating seleoprotein synthesis, thereby reducing cancer risk [26]

. The evidence

suggests that down-regulation of SeP-1 expression leads to oxidative stress and

usually to increased activity of GPx in tumorous tissue, probably as a result of a

feedback mechanism [26,�27]

. These cumulative data lead to the conclusion that the

activity of several selenoproteins is interrelated in maintaining homeostasis.

12.3� Selenoproteins: Modes of Action and Thyroid Cancer

The human thyroid gland contains more Se per gram of tissue than any other

organ [28-30]

. This feature, together with the fact that all three deiodinases are

12� Selenoproteins and Thyroid Cancer 178

selenoproteins, underlines the fundamental role of Se for thyroid function. Besides

deiodinases, several other selenoproteins are expressed in thyrocytes. Three GPxs,

mainly cGPx, which is detected at high levels, pGPx and PHGPx as well as Trx,

SeP and Sel15 are expressed in thyroid tissue [29, 31]

. More precisely, GPx is

located in the thyrocytes and follicular tissues, its main functions being to protect

the thyroid from the deleterious effects of hydrogen peroxide (H2O

2) and to

control iodination [32]

. Trxs utilizing NADPH as a co-factor constitute a very

strong oxidoreductare system that regulates the cellular redox state and cell

signaling, while also being implicated together with phospholipid hydroperoxide

(GPx4) in the inhibition of apoptosis [31, 33]

. GPx3 mRNA is localized to the

thyrocytes where it exhibits the highest expression levels; in thyroid cancer

samples it is usually down-regulated as compared to controls [31]

. Se supply is vital

both for maintenance of the functioning of thyroid GPxs and Trxs and for

protection of the gland from oxidative damage [34, 35]

. Low Se levels may indicate

impaired detoxifying capacity, this possibly accounting for the increased

production of ROS by the mutated RAS oncogene [36]

. If the antioxidant defense is

impaired, the increased oxidative stress can lead to DNA damage, followed by an

increased spontaneous mutation rate which predisposes the subject to tumori-

genesis [37]

. Therefore, any reduction in the levels of selenium intake will likely

affect several selenoproteins in the thyroid, thus potentially raising the risk of

thyroid cancer. When Se levels exceed the required amounts used for the

generation of GPx, they considerably increase the cytotoxic effects of natural

killers while enhancing the expression of interleukin-2 receptor [38]

. Thus, the

selenoproteins, which are exceptional in the distinctiveness of their separate

modes of regulation by signaling cascades, also impact thyrocyte proliferation and

behavior [28]

.

A relation between low serum Se levels and thyroid cancer was reported in the

1990’s when the Janus Serum Bank, a long-term project investigating parameters

which might be associated with cancerogenesis, found that low serum Se levels

constitute a risk factor for thyroid cancer [39]

. Parallel findings were derived from a

case-control study conducted in 43 subjects who developed thyroid cancer on an

average of 4.8 years after blood sampling: the odds ratio for thyroid cancer was

observed to have increased from 1 to 4 levels above or equal to 1.65 mmol/L to

7.7 for Se levels equal to, or less than, 1.25 mmol/L [40]

.

Despite these findings, a direct causal relation between Se deficiency and

thyroid cancer has not been established, nor has any association between the

polymorphism of GPx1 and thyroid cancer been conclusively shown [41]

.

On the other hand, many thyroid diseases, including thyroid cancer, display a

geographical pattern, this suggesting the etiological implication of iodine and

selenium both of which are essential for thyroid hormone metabolism and

action [42]

. Iodine deficiency may result in increased TSH secretion, increased

EGF-stimulated thyroid cell proliferation, a decreased TGFbeta-1 production rate

and increased angiogenesis, all these constituting paths that promote tumorgenesis [43]

,

while concomitant Se deficiency is highly likely to amplify these phenomena.

Inflammation generally acts as a double-edged sword in the pathogenesis of

12.3� Selenoproteins: Modes of Action and Thyroid Cancer� 179

cancer. A prolonged presence of pro-inflammatory cytokines, such as that

occurring in overexpression of interleukin-1beta, contributes to the dysregulation

of tumor-specific immunity. The RET/PTC3 fusion protein, an oncogene that is

widely expressed during the development of thyroid cancer, can activate the

nuclear factor kappa-B (NF-κΒ) transcription to stimulate the secretion of pro-

inflammatory cytokines [44,�45]

. All inflammatory states may trigger NF-κB by

producing ROS, while monomethylated Se compounds inhibit the activation of

NF-κB via GPx. A low Se and/or iodine intake may promote a pro-inflammatory

milieu that can modulate NF-κB, which is then associated with low apoptosis and

more aggressive histology [46]

. Recent data also indicate that Se deficiency

modifies xenobiotic metabolism through the Nrf2-antioxidant response element

and causes cytosolic oxidative stress [47]

.

Another anticancer mechanism is the induction of apoptosis and the resultant

arrest of the cell cycle during the G1 phase by Se compounds [48]

. It has recently

been reported that Se at micromolar concentrations inhibits cell growth and

invasion by inducing apoptosis in transformed prostate cancer cells [48]

. Also

noteworthy is the role played in these cellular processes by protein kinase C

(PKC), and particularly PKCepsilon that is sensitive to the redox-active form of

Se [48]

. Since PKC is negatively correlated with cellular sensitivity to Se, PKC

overexpression may arrest the inhibitory action of Se on cell transformation and

induction of apoptosis. However, although these effects have been observed in

prostate cancer, there is still uncertainty as to whether the same mechanisms are

operative in thyroid cancer.

Se can reduce DNA damage, as has been suggested in a New Zealand study of

men determined to be at risk of prostate cancer based on the level of prostate-

specific antigen. An inverse relationship was documented between the overall

accumulated DNA damage in leucocytes and serum Se concentration [49, 17]

.

A synopsis of the anti-cancer effects of Selenium and its compounds is

presented in Table 12.2.

Table 12.2� Molecular pathways and the multiple anti-cancer effects of selenium and its compounds

(Current References)

Pathways and mechanisms References

Se compounds act as a depot

for selenoproteins

Brigelius-Flohé [5]

Rayman [17]

Reduction of oxidative stress Krohn [36]

Induction of apoptosis Burk [46]

, Zeng [47]

Gundimeda [48]

Inhibition of angiogenesis Jackson [50]

, Zeng [51]

Induction of phase 2 enzymes*

Brigelius-Flohé [5]

Reduction of inflammation Ravasco, Duntas [44, 45]

Chemotherapeutic efficacy acting via p53 Fischer [52]

*

The phase 2 enzymes defense system is regulated by Nrf2

The role of Trxs in the development and prevention of thyroid cancer is still a

12� Selenoproteins and Thyroid Cancer 180

matter of intense research since Trxs are, together with GPxs selenoproteins, of

central importance in the regulation of the cellular redox state. Inhibition of Trx-

receptor by its selective inhibitor aurafontin and pretreatment with selenite

induced a dramatic deterioration in both aurafontin cytoxicity and the cellular

redox state [53]

.

Currently, implementation of Se compounds in the form of L-seleno-methionine

or methylselenocysteine as selective modulators of anticancer drugs has attracted a

good deal of interest [54]

. This novel co-adjuvant therapy may allow an increased

dose of chemotherapeutics, enhance anti-tumor activity and cure rates and reverse

drug resistance.

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