Affiliations of authors: Cancer Prevention Studies Branch (PRT) and Division of Cancer Prevention (HLP), National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Clinical Cancer Prevention, Division of Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, TX (SML).
Correspondence to: Scott M. Lippman, MD, Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 236, Houston, TX 77030 (e-mail: slippman{at}mdanderson.org)
The role of the essential trace element selenium in prostate cancer was first (and last) editorialized in the Journal in 1998 in conjunction with the report of the first large prospective observational study of selenium and the risk of advanced prostate cancer (1,2). Although the principals for the 1998 study were the same as those for the observational study by Li et al. (3) in this issue of the Journal, much has changed in the basic scientific understanding of selenium. The onion, an allium vegetable that concentrates selenium, is an apt metaphor for the scientific work of peeling back the layers of molecular effects and mechanisms underlying the strong selenium epidemiology in the prostate.
The past 6 years have seen the publication of seven prospective epidemiologic studies of selenium status and prostate cancer (including the study in this issue of the Journal) (28), with a collective total of nearly 2000 case subjects. The studies involved low [Europe (8)], moderate [Maryland (5)], and high [Hawaii (4)] selenium status populations, and all but one found a protective effect associated with higher concentrations of selenium. Furthermore, low plasma selenium levels are associated with increases in other cancers and human diseases (9). Although the findings of the observational studies have been encouraging and consistent regarding the prostate, the most powerful evidence to date for the beneficial effect of selenium is the 49% reduction in prostate cancer incidence in the randomized, placebo-controlled Nutritional Prevention of Cancer (NPC) trial, in which selenium was administered at 200 µg/day (10,11). On the basis of the NPC trial, epidemiologic studies, a randomized prevention trial in China of selenium in combination with other minerals and vitamins (12), and early preclinical data (1317) available in 2000, selenium was included in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) in 32 400 men to definitively test the role of supplementation with selenium and/or vitamin E in the prevention of prostate cancer (18).
Before addressing the basic science behind the results of these selenium studies, we will highlight two important aspects of the study by Li et al. (3): selenium effects by stage of disease and selenium effects by baseline prostate-specific antigen (PSA) levels. The finding that selenium was associated with a reduced risk of advanced prostate cancer (stage C or D) is consistent with the findings of three of four other epidemiologic studies (24) that assessed this variable and supports the hypothesis of Li et al.that selenium affects tumor progression rather than premalignancy. This finding also is consistent with the observation that selenium was associated with a greater reduction in risk for men with PSA levels of greater than 4 ng/mL than for men with PSA levels of 4 ng/mL or less. These stage and PSA associations seemingly are at odds, however, with the NPC findings that the protection conferred by selenium was largely due to reduced local disease and was limited almost exclusively to men with PSA levels of 4 ng/mL or less (11). The discrepancy between the results of Li et al. (3) and those of the NPC may be due, in part, to differences in study designs (i.e., observation versus intervention) and to enormous differences in the doses and durations of exposure that were assessed.
Although associated with lower PSA levels, the risk reduction in the NPC study does not necessarily conflict with the hypothesis of Li et al. (3) that selenium slows tumor progression (3). First, the curves of prostate cancer incidence for the placebo and selenium arms separated early in the NPC study, which would not be expected for effects on the decades-long process of premalignant tissue transforming into malignant tissue. Second, prostate cancer is far more prevalent in men with lower PSA levels than is generally thought. Thompson et al. (19) recently reported that the prevalence of prostate cancer (detected by biopsy after 7 years of close follow-up) was surprisingly high at 15% among 3820 men with PSA levels of 4.0 ng/mL or less on the placebo arm of the Prostate Cancer Prevention Trial (PCPT). This rate begins to approach that reported heretofore for men with PSA levels of 410 ng/mL (20), suggesting that future exploratory analyses probably should set the PSA cut point substantially below 4 ng/mL. Therefore, the NPC result may have been based on slowing or halting the progression of microscopic, subclinical prostate cancer. Moreover, transformation was likely prevented or delayed, as suggested by the durability of the separation of the prostate cancer curves. This important issue of preventing or delaying transformation to cancer versus treating subclinical, microscopic cancer has been debated since publication of the primary reports of other large-scale trials, including the PCPT (19,21,22). In either case, the effect of selenium would be beneficial.
Molecular and cellular bases for the published observations of selenium preventive activity in the prostate are emerging and providing biologic plausibility for clinical prostate cancer prevention trials of selenium, such as the SELECT. The primary nutritional role of selenium in regulating the redox state and energy metabolism involves its incorporation as selenocysteine, the 21st amino acid, into selenoproteins. Selenium potentially affects cancer development through its known effects on oxidative stress, DNA repair, inflammation, apoptosis, proliferation, carcinogen metabolism, testosterone production, angiogenesis, fat metabolism, and immune function (9,2325). The potential for these effects in the prostate is supported by data showing that selenium accumulates, reduces DNA damage, and increases apoptosis in the prostates of older dogs and accumulates in human prostates (26,27). Natural organic (e.g., selenomethionine) and inorganic (e.g., selenite) forms of selenium are metabolized via different pathways into selenide, which can then be either phosphorylated and ultimately incorporated as selenocysteine into active selenoproteins or methylated into active metabolites, such as methylselenol (28,29). Therefore, selenium effects can be indirect (via incorporation into selenoproteins) and/or direct (via selenium metabolites). Direct selenium effects, including differential effects on normal versus malignant prostate cells, vary with different metabolites and have been observed in vitro at pharmacologically achievable concentrations of selenium. The most active known metabolites in preclinical studies are natural methylated compounds (e.g., methylselenol) and synthetic organoselenium compounds (e.g., 1,4 phenylenebis(methylene)selenocyanate) (28,29). Scientists are just beginning to examine the molecular basis of direct selenium effects in prostate cancer in studies that involve molecular targets such as manganese superoxide dismutase, p21, caspase-8, NF-B, protein kinase C, and the androgen receptor (17,25,3034).
Indirect selenium effects via the enzymatic functions of certain selenoproteins have been analyzed more extensively. The generation of selenocysteine from selenide and its co-translational incorporation into selenoproteins is a complex process involving selenophosphate synthetase, selenocysteine synthase, selenocysteinyl-tRNASec synthase, and the recognition of selenocysteine by selenocysteine insertion sequence element consensus structures within the 3'-untranslated region of selenoprotein mRNA (35). Besides their well-known effects (e.g., of glutathione peroxidase [GPX]) on intracellular redox, selenoproteins have many other activities, which can vary by cell type, physiologic status, or the presence or absence of incorporated selenocysteine. For example, the selenoprotein thioredoxin reductase without (but not with) selenocysteine appears to induce apoptosis and inhibit growth in certain cell types (36,37). There are questions about the precise role of selenoproteins in selenium cancer prevention studies because GPX, which is the most thoroughly studied of these proteins, is saturated at much lower selenium levels than are required for preventive activity (26). The saturation and activity profiles of newly identified selenoproteins or of recently described single nucleotide polymorphisms (SNPs) of known selenoproteins, however, are not known (23). Bioinformatics and comparative phylogenetics analyses (using selenocysteine insertion sequence element consensus structures) recently described 25 different human proteins containing selenocysteine (38), of which two, Sep15 and Selenoprotein P, are implicated in prostate cancer development and prevention (39,40). We have only just begun to study the functions and genetic variations of these different selenoproteins and how these variations affect disease.
Genetic variations (e.g., SNPs) of only four selenoproteins (Sep15, Selenoprotein P, GPX1, and GPX4) have been identified thus far (4043), and hundreds more variants will likely be found. Different selenoprotein SNPs may respond differently to selenium supplementation, suggesting their potential association with pharmacogenetic differences in selenium's preventive effects (44). Epidemiologic studies, including two studies of the variant allele for the cellular antioxidant GPX1 [which was associated with increased risk for both lung (45) and breast (46) cancers] and a study of a GCG repeat polymorphism in GPX1 [which was not associated with prostate cancer (47)], have linked genetic variation to disease. The mounting epidemiologic data on high rates of disease in association with low selenium status provide powerful global evidence supporting the recent laboratory data on the functionality of selenoproteins. Selenoprotein transgenic and conditional knockout models currently in development in mice will help clarify the role of selenium and selenoproteins in cancer risk and prevention (48).
Studies of molecular and cellular effects of selenium in prostate carcinogenesis will contribute to important future hypotheses, such as those for correlative studies planned in the ongoing SELECT (49). The SELECT prospectively established a biorepository for research specimens, including serum and white blood cells, from its planned 32 400 participants. The SELECT is also collecting ancillary data, such as information on diet, supplements, and other medicines, and clinical data on several important prespecified secondary endpoints, such as the incidences of lung and colorectal cancer and heart and Alzheimer disease. The SELECT data and biospecimens and the insights from ongoing mechanistic selenium studies should advance our understanding of selenium in prostate carcinogenesis and many other diseases. The rapidly evolving field of selenium and selenoprotein biology promises to identify novel molecular targets for preventing or delaying various cancers and cardiovascular, neurodegenerative, and other diseases, in which selenium appears to play an important role (9,23,50).
The new epidemiologic data on selenium from Li et al. (3) continue to support the initial impressions of this agent's tremendous potential as a prostate cancer preventive agent. The emerging laboratory data greatly strengthen the biologic plausibility for this optimism and for the ongoing randomized clinical selenium trials, which ultimately will be necessary to define the potentially complex riskbenefit profile of this promising preventive agent (22,51). Meanwhile, science will continue peeling back layer after layer of the enormously deep and complex onion of selenium effects in the prostate.
NOTES
S. M. Lippman holds the Anderson Clinical Faculty Chair for Cancer Treatment and Research at The University of Texas M. D. Anderson Cancer Center and is supported, in part, by Public Health Service grant CA16672 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
REFERENCES
1 Taylor PR, Albanes D. Selenium, vitamin E, and prostate cancerready for prime time? J Natl Cancer Inst 1998;90:11845.
2 Yoshizawa K, Willett WC, Morris SJ, Stampfer MJ, Spiegelman D, Rimm EB, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst 1998;90:121924.
3 Li H, Stampfer MJ, Giovannucci EL, Morris JS, Willett WC, Gaziano JM, et al. A prospective study of plasma selenium levels and prostate cancer risk. J Natl Cancer Inst 2004;96:696703.
4 Nomura AM, Lee J, Stemmermann GN, Combs GF Jr. Serum selenium and subsequent risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2000;9:8837.
5 Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst 2000;92:201823.
6 Brooks JD, Metter EJ, Chan DW, Sokoll LJ, Landis P, Nelson WG, et al. Plasma selenium level before diagnosis and the risk of prostate cancer development. J Urol 2001;166:20348.[ISI][Medline]
7 Goodman GE, Schaffer S, Omenn GS, Chen C, King I. The association between lung and prostate cancer risk, and serum micronutrients: results and lessons learned from beta-carotene and retinol efficacy trial. Cancer Epidemiol Biomarkers Prev 2003;12:51826.
8 van den Brandt PA, Zeegers MP, Bode P, Goldbohm RA. Toenail selenium levels and the subsequent risk of prostate cancer: a prospective cohort study. Cancer Epidemiol Biomarkers Prev 2003;12:86671.
9 Rayman MP. The importance of selenium to human health. Lancet 2000;356:23341.[CrossRef][ISI][Medline]
10 Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996;276:195763.[Abstract]
11 Duffield-Lillico AJ, Dalkin BL, Reid ME, Turnbull BW, Slate EH, Jacobs ET, et al. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU Int 2003;91:60812.[ISI][Medline]
12 Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;85:148392.[Abstract]
13 Schrauzer GN. Anticarcinogenic effects of selenium. Cell Mol Life Sci 2000;57:186473.[ISI][Medline]
14 Behne D, Weiler H, Kyriakopoulos A. Effects of selenium deficiency on testicular morphology and function in rats. J Reprod Fertil 1996;106:2917.[Abstract]
15 Redman C, Xu MJ, Peng YM, Scott JA, Payne C, Clark LC, et al. Involvement of polyamines in selenomethionine induced apoptosis and mitotic alterations in human tumor cells. Carcinogenesis 1997;18:1195202.[Abstract]
16 Redman C, Scott JA, Baines AT, Basye JL, Clark LC, Calley C, et al. Inhibitory effect of selenomethionine on the growth of three selected human tumor cell lines. Cancer Lett 1998;125:10310.[CrossRef][ISI][Medline]
17 Menter DG, Sabichi AL, Lippman SM. Selenium effects on prostate cell growth. Cancer Epidemiol Biomarkers Prev 2000;9:117182.
18 Klein EA, Lippman SM, Thompson IM, Goodman PJ, Albanes D, Taylor PR, et al. The selenium and vitamin E cancer prevention trial. World J Urol 2003;21:217.[ISI][Medline]
19 Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:21524.
20 Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991;324:115661.[Abstract]
21 Lippman SM, Hong WK. Cancer prevention by delay. Clin Cancer Res 2002;8:30513.
22 Lippman SM, Hong WK. Cancer prevention science and practice. Cancer Res 2002;62:511925.
23 Hatfield DL, Gladyshev VN. How selenium has altered our understanding of the genetic code. Mol Cell Biol 2002;22:356576.
24 Seo YR, Kelley MR, Smith ML. Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. Proc Natl Acad Sci U S A 2002;99:1454853.
25 Meuillet E, Stratton S, Cherukuri DP, Goulet AC, Kagey J, Porterfield B, et al. Chemoprevention of prostate cancer with selenium: an update on current clinical trials and preclinical findings. J Cell Biochem 2004;91:44358.[CrossRef][ISI][Medline]
26 Waters DJ, Shen S, Cooley DM, Bostwick DG, Qian J, Combs GF Jr, et al. Effects of dietary selenium supplementation on DNA damage and apoptosis in canine prostate. J Natl Cancer Inst 2003;95:23741.
27 Sabichi AL, Lee JJ, Taylor RJ, Thompson IM Jr, Miles BJ, Basler JW, et al. Selenium accumulates in prostate tissue of prostate cancer patients after short-term administration of l-selenomethionine. Proc Am Assoc Cancer Res 2002;43:10078.
28 Tapiero H, Townsend DM, Tew KD. The antioxidant role of selenium and seleno-compounds. Biomed Pharmacother 2003;57:13444.[CrossRef][ISI][Medline]
29 Ip C, Thompson HJ, Zhu Z, Ganther HE. In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention. Cancer Res 2000;60:28826.
30 Zhong W, Oberley TD. Redox-mediated effects of selenium on apoptosis and cell cycle in the LNCaP human prostate cancer cell line. Cancer Res 2001;61:70718.
31 Jiang C, Wang Z, Ganther H, Lu J. Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells. Cancer Res 2001;61:306270.
32 Venkateswaran V, Klotz LH, Fleshner NE. Selenium modulation of cell proliferation and cell cycle biomarkers in human prostate carcinoma cell lines. Cancer Res 2002;62:25405.
33 Dong Y, Zhang H, Hawthorn L, Ganther HE, Ip C. Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by oligonucleotide array. Cancer Res 2003;63:529.
34 Dong Y, Lee SO, Zhang H, Marshall J, Gao AC, Ip C. Prostate specific antigen expression is down-regulated by selenium through disruption of androgen receptor signaling. Cancer Res 2004;64:1922.
35 Driscoll DM, Copeland PR. Mechanism and regulation of selenoprotein synthesis. Annu Rev Nutr 2003;23:1740.[CrossRef][ISI][Medline]
36 Gallegos A, Berggren M, Gasdaska JR, Powis G. Mechanisms of the regulation of thioredoxin reductase activity in cancer cells by the chemopreventive agent selenium. Cancer Res 1997;57:496570.[Abstract]
37 Anestal K, Arner ES. Rapid induction of cell death by selenium-compromised thioredoxin reductase 1 but not by the fully active enzyme containing selenocytsteine. J Biol Chem 2003:278:1596672.
38 Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R, et al. Characterization of mammalian selenoproteomes. Science 2003;300:143943.
39 Calvo A, Xiao N, Kang J, Best CJ, Leiva I, Emmert-Buck MR, et al. Alterations in gene expression profiles during prostate cancer progression: functional correlations to tumorigenicity and down-regulation of selenoprotein-P in mouse and human tumors. Cancer Res 2002;62:532535.
40 Kumaraswamy E, Malykh A, Korotkov KV, Kozyavkin S, Hu Y, Kwon SY, et al. Structure-expression relationships of the 15-kDa selenoprotein gene. Possible role of the protein in cancer etiology. J Biol Chem 2000;275:355407.
41 Moscow JA, Schmidt L, Ingram DT, Gnarra J, Johnson B, Cowan KH. Loss of heterozygosity of the human cytosolic glutathione peroxidase I gene in lung cancer. Carcinogenesis 1994;15:276973.[Abstract]
42 Al Taie OH, Seufert J, Mork H, Treis H, Mentrup B, Thalheimer A, et al. A complex DNA-repeat structure within the Selenoprotein P promoter contains a functionally relevant polymorphism and is genetically unstable under conditions of mismatch repair deficiency. Eur J Hum Genet 2002;10:499504.[CrossRef][ISI][Medline]
43 Villette S, Kyle JA, Brown KM, Pickard K, Milne JS, Nicol F, et al. A novel single nucleotide polymorphism in the 3' untranslated region of human glutathione peroxidase 4 influences lipoxygenase metabolism. Blood Cells Mol Dis 2002;29:1748.[CrossRef][ISI][Medline]
44 Hu YJ, Korotkov KV, Mehta R, Hatfield DL, Rotimi CN, Luke A, et al. Distribution and functional consequences of nucleotide polymorphisms in the 3'-untranslated region of the human Sep15 gene. Cancer Res 2001;61:230710.
45 Ratnasinghe D, Tangrea JA, Andersen MR, Barrett MJ, Virtamo J, Taylor PR, et al. Glutathione peroxidase codon 198 polymorphism variant increases lung cancer risk. Cancer Res 2000;60:63813.
46 Hu YJ, Diamond AM. Role of glutathione peroxidase 1 in breast cancer: loss of heterozygosity and allelic differences in the response to selenium. Cancer Res 2003;63:334751.
47 Kote-Jarai Z, Durocher F, Edwards SM, Hamoudi R, Jackson RA, Ardern-Jones A, et al. Association between the GCG polymorphism of the selenium dependent GPX1 gene and the risk of young onset prostate cancer. Prostate Cancer Prostatic Dis 2002;5:18992.[CrossRef][ISI][Medline]
48 Kumaraswamy E, Carlson BA, Morgan F, Miyoshi K, Robinson GW, Su D, et al. Selective removal of the selenocysteine tRNA [Ser]Sec gene (Trsp) in mouse mammary epithelium. Mol Cell Biol 2003;23:147788.
49 Hoque A, Albanes D, Lippman SM, Spitz MR, Taylor PR, Klein EA, et al. Molecular epidemiologic studies within the selenium and vitamin E cancer prevention trial (SELECT). Cancer Causes Control 2001;12:62733.[CrossRef][ISI][Medline]
50 Benton D. Selenium intake, mood and other aspects of psychological functioning. Nutr Neurosci 2002;5:36374.[CrossRef][ISI][Medline]
51 Duffield-Lillico AJ, Slate EH, Reid ME, Turnbull BW, Wilkins PA, Combs GF Jr, et al. Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial. J Natl Cancer Inst 2003;95:147781.
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