Oxidative stress-related aging: A role for prostate cancer?

Biochimica et Biophysica Acta 1795 (2009) 83–91

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Biochimica et Biophysica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a c a n

Review

Oxidative stress-related aging: A role for prostate cancer? Alba Minelli a,⁎, Ilaria Bellezza a, Carmela Conte a, Zoran Culig b a b

Dipartimento di Medicina Sperimentale Scienze Biochimiche, Sezione Biochimica Cellulare, Università di Perugia, via del Giochetto, 06123 Perugia, Italy Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria

a r t i c l e

i n f o

Article history: Received 15 July 2008 Received in revised form 21 November 2008 Accepted 26 November 2008 Available online 11 December 2008 Keywords: p53 Sexual hormone Growth factor Microenvironment Vitamin D Changes in oxidative defence system Inflammation

a b s t r a c t Prostate cancer has the highest prevalence of any non-cutaneous cancer in the human body and essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. Aging, considered as an impairment of body functions over time, caused by the accumulation of molecular damage in DNA, proteins and lipids, is also characterized by an increase in intracellular oxidative stress due to the progressive decrease of the intracellular ROS scavenging. The aging damage may eventually appear in agerelated health issues, which have a significant impact on the independence, general well-being and morbidity of the elderly. The association of aging with prostate cancer is undisputable as well as the association of aging with oxidative stress. Nevertheless, supportive evidence linking an increase in oxidative stress with prostate cancer is still scarce. This review is a comprehensive, literature-based analysis of the association of human prostate cancer with oxidative stress. The objective was to examine the involvement of reactive oxygen species in the mechanisms of prostatic carcinogenesis since the understanding of risk factors for prostate cancer has practical importance for public health, genetic and nutritional education, and chemoprevention. © 2008 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . Epidemiology of prostate cancer . . . . . . . . . . Molecular links between aging and oxidative stress in 3.1. p53 . . . . . . . . . . . . . . . . . . . . . 3.2. Sexual hormones . . . . . . . . . . . . . . 3.3. Growth factors . . . . . . . . . . . . . . . 3.4. Microenvironment . . . . . . . . . . . . . 3.5. Vitamin D . . . . . . . . . . . . . . . . . 3.6. Changes in oxidative defence system . . . . . 3.7. Inflammation . . . . . . . . . . . . . . . . 4. Aging, oxidative stress and prostate cancer . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Aging, defined as a progressive decline in the ability of the organism to resist stress, damage, and disease, is an inexorable process in humans and is associated with many complex diseases, i.e. cancer, diabetes, cardiovascular diseases and neurodegenerative ⁎ Corresponding author. Fax: +39 075 585 7442. E-mail address: [email protected] (A. Minelli). 0304-419X/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.bbcan.2008.11.001

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disorders [1]. Better understanding of the aging process and the capacity to intervene to prevent disease is becoming a healthcare priority since the population demographics of most Western countries are changing rapidly and the proportion of older individuals is rising steadily, due to falling birth rates and declining mortality. In 2004 people over 65 represented 12.4% of the population in the USA, and the percentage will rise to 20% by 2030 [2].Several theories, mainly divided in two general categories, i.e. stochastic and developmental-genetic (Scheme 1), explain the

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Scheme 1. Theories of aging.

aging phenomenon but no unifying theory may be valid, since the mechanisms of aging are quite distinct in different organisms, tissues, and cells. Therefore it is still not well understood why organisms age and why the aging process can vary so much in speed and quality from individual to individual. Stochastic theories propose that aging is caused by damages that occur randomly to vital molecules and eventually accumulate to result in the physiological decline associated with aging [3]. On the other hand, developmentalgenetic theories consider the process of aging as a part of the genetically programmed and controlled development and maturation. Recent studies at molecular genetic level have suggested that cellular senescence may be antagonistically pleiotropic because it prevents tumourigenesis, but also contributes to organism aging. Therefore aging may be the price we pay to avoid cancer [4]. A more unifying vision of aging has been proposed by Martin and Sheaff [2], who discussed the factors involved in the aging process. They showed that the pathways involved in aging often share features with disease processes. Recently, Xue et al. [5] have experimentally validated by Caenorhabditis elegans lifespan analysis that protein– protein interactions affect aging/longevity implicating a potential molecular basis for the stochastic nature of aging. The spectacular lifespan extension in certain mutants of nematodes, fruit flies, or mice suggested that aging may be a regulated process under the control of a few ‘aging genes’, involved in the insulin signalling pathway and in the expression of certain ‘silent informationregulating proteins’ or sirtuins [6,7]. Sirtuins are a conserved family of proteins found in all domains of life. The founding member of the sirtuin family, Sir2p in yeast or SIRT1 in mammals, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals [8]. The vital role that the sirtuins play in cellular metabolic control indicated that they might be important determinants of whole-body metabolism and protect against many chronic diseases associated with metabolic dysfunction and cancer [9–11]. On the other hand, there is a growing body of evidence supporting the ‘free-radical theory of aging’, which predicts that the lifespan of an organism could be increased by augmenting antioxidant defenses. Oxygen free radicals (ROS) are formed endogenously from normal oxygen-

utilizing metabolic processes and play an essential role in the aging process [12,13]. During mitochondrial respiration, electrons are extracted from reduced substrates and are transferred to molecular oxygen (O2) through a chain of enzymatic complexes (I to IV). Partial reduction of O2, which results in the generation of ROS, can occur if O2 interacts with the electron-transfer chain upstream of complex IV. Some electrons can escape from the mitochondrial electron-transfer chain, especially from complexes I and III, and react with O2 to form U the superoxide radical (O2−) [14,15]. These oxygen-derived species can react with macromolecules in a self-perpetuating manner thereby amplifying the effect of the initial free radical attack [16]. One specific ROS, i.e. hydrogen peroxide (H2O2), is produced by mitochondria through a specialized enzyme to control cellular growth and death U [15]. The O2− is metabolized by SOD to form oxygen and H2O2, which, U in turn, can form the extremely reactive hydroxyl radical (HO ). Oxidative damage increases during aging [17,18]. In agreement with the proposal that mitochondria are central to aging, it was discovered that mtDNA deletions and point mutations are induced by oxidative stress and accumulate with age [19]. The realization that many other ROS, i.e. peroxides and aldehydes, which are not technically free radicals, also play a role in oxidative damage in cells, led to a modification of the free radical theory, as the oxidative stress theory of aging [16]. A chronic state of oxidative stress exists in cells of aerobic organisms even under physiological conditions because of an imbalance between prooxidants and antioxidants. To lessen the consequences of damage by ROS, cells have evolved complex defence mechanisms, including enzymes and various nonenzymatic antioxidants that act to detoxify the noxious molecules. The fact that the ratio of superoxide dismutase (SOD) specific activity to specific metabolic rate increases with increasing maximum lifespan potential (MLSP) [20] led to propose an important correlation between lifespan and energy metabolism and between oxidative stress and antioxidant defence systems. Many mammals show modest sex-specific differences in lifespan that might be related to the fact that hormonallydriven metabolism in males is set at higher levels than in females and higher metabolism produces larger quantities of ROS [21–23]. ROS can also be important signalling molecules [15,24] and there is increasing evidence for signalling networks that coordinately “manage” the levels of ROS within the cell. Potential examples includes FOXO3a [25], p66SHC [26], Nrf2-ARE [27], and p53 [28]. There are only a few examples of genetic manipulations in mice that directly decrease

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oxidative damage and result in extended lifespan [16]. The most remarkable examples are mice deficient in the mitochondrial redox protein p66SHC [29] and mice that overexpress catalase in the mitochondria [30] both displaying delayed aging. All data support the proposal that oxidative damage is, al least, one probable cause of aging [31]. Scientific and clinical research is mainly focused on elucidating the mechanisms involved in the complex cross-talk between aging and oxidative stress for future clinical recommendations in the prevention/treatment of cancer and other aging-related diseases, extremely prevalent problems in our aging population.

indicate that intake of antioxidants offers protection against PCa but the exact mechanisms of PCa development and progression in humans remain to be completely understood.

2. Epidemiology of prostate cancer

p53 pathway impacts upon longevity and aging-related diseases. The efficiency of the p53 response to stress declines significantly with age in mice, and the time of onset of this decreased p53 response correlates with the lifespan of mice [40]. Given the crucial role of the p53 in tumour prevention, this decline in p53 activity at older ages in animals could contribute to the observed dramatic increases in cancer frequency, and provides a plausible explanation for the correlation between tumourigenesis and aging in addition to the accumulation of DNA mutations over lifetime [40]. p53 is found completely lost or mutated almost exclusively in advanced PCa [41]. Similarly to many other factors that control cell proliferation and apoptosis, p53 has been identified as sirtuin substrate. It has several acetylation sites, and its hyperacetylation stabilizes and activates it to trigger apoptosis and cell-cycle arrest. Conversely, the deacetylation of p53 by SIRT1 is predicted to induce its destruction by the ubiquitin-mediated pathway [10] suggesting that SIRT1 may increase the risk of cancer. High expression of SIRT1 is a common and relevant pathologic event in PCa [42]. Other mechanisms have opposing effects on cancer and aging; i.e., protecting from cancer but promoting aging. These mechanisms include telomere shortening [43] and the derepression of the INK4a/ ARF locus [44]. Cellular senescence mediated by telomere dysfunction has long been proposed as a p53-dependent tumour suppressor mechanism. p53 activation leads to cancer regression via senescence or apoptosis [45]. Several data [31] indicate that senescent cells can be efficiently cleared from the organism and, therefore, senescenceinducing mechanisms are not necessarily pro-aging. Although convergent and divergent mechanisms between cancer and aging have been proposed, there is a general consensus that the accumulation of cellular damage is the initiating event of both processes. ROS are decreased by improving the efficiency of energy consumption [46] and p53, a master sensor of damage, capable of triggering repair and defence responses [28], decreases ROS accumulation via regulation of the expression of a number of genes associated with the metabolism of ROS. Therefore mechanisms or interventions that decrease ROS or improve p53 activity converge in providing protection against cancer. p53 regulates the expression of multiple antioxidant genes and p53−/ − mice have elevated oxidative stress [28]. The importance of this oxidative stress is emphasized by the fact that the life span and carcinogenesis in p53−/− mice can be rescued by pharmacological doses of the antioxidant N-acetylcysteine [28]. Although the role of H2O2 in biological processes is still to be fully elucidated, there is a growing body of evidence that suggests that an increase in the cellular levels of H2O2 may play, directly or indirectly, a key role in malignant transformation, and sensitise cancer cells to H2O2-induced cell death [47]. The tumour suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) is frequently mutated or deleted in various human cancers. PTEN, localised predominantly in the cytoplasm, negatively regulates the phosphatidylinositol 3kinase-AKT signalling pathway. When localised in the nucleus, it binds and regulates p53 protein level and transcription activity. Oxidative stress inhibits PTEN nuclear export leading to p53-mediated growth arrest, cell death, and reduction of ROS production [48]. Chen et al., by examining the functional relation between loss of the PTEN

Prostate cancer (PCa) is the most common non-cutaneous malignancy in men in Western countries and is strongly agedependent. About 81% of patients with PCa are over 65 years of age whereas in the age group 45–54 the incidence has been reported as 6 per 100,000/year [32]. In Europe, there are about 80,000 deaths a year from PCa whereas in the United States 27,050 deaths over 218,890 new cases in 2007 have been reported (www.cancer.gov). Almost all PCas (95%) are adenocarcinoma that originate in glandular tissue. PCa is often a slow growing tumour characterized by a 10-year cancerspecific mortality of 24%. Clinical PCa is extremely rare in men ages b40, occurring with a frequency of 1 in 10,000 individuals [33]. The incidence increases dramatically over the ensuing decades. The relationship between PCa incidence and aging is consistent across ethnic and racial groups. The prevalence of latent or indolent prostate carcinoma also increases in a dramatic fashion with aging. Sakr et al. [34] systematically examined prostate glands from young males and identified prostatic intraepithelial neoplasia in 0%, 9%, 20%, and 44%, and foci of histologic cancer in 0%, 0%, 27%, and 34% in the second, third, fourth, and fifth decades of age, respectively. Control of normal prostate secretory cell growth and function is maintained by a finely tuned balance between cellular concentrations of sex steroid hormones and locally produced paracrine and autocrine growth factors. Treatment using androgen ablation strategies is initially successful in most cases; however, highly aggressive and androgenindependent tumours may recur, for which treatment is mainly palliative. Epidemiological data showing ethnic and geographic variations in PCa incidence and mortality have suggested that the consumption of dietary anti-oxidants factors, i.e. vitamins D and E, soy, lycopene and selenium, may be protective [35]. The α-Tocopherol and β-Carotene (ATBC) clinical trial, involving 29,133 male smokers receiving α-tocopherol and β-carotene, ATBC in combination, or a placebo, showed that oxidants may play a role in the aetiology of PCa or precursor lesions [35,36]. Long-term daily supplementation with 50 mg of α-tocopherol was associated with a substantial reduction in the incidence of and mortality from PCa. In this study, a reduction in clinically overt cancers appeared soon after the onset of supplementation, suggesting that α-tocopherol influences the transformation phase of cancer from latent to clinical. αTocopherol had no effect on advanced PCa, since the time from diagnosis of clinical PCa to death was not lengthened compared with nonrecipients. PCa incidence was 23% higher among men who received β-carotene compared with those who did not. These effects are unlikely to have been biased by selection or end point assessment [36]. The findings from epidemiologic studies are conflicting, since in two other large chemoprevention trials, the Beta-Carotene and Retinol Efficacy Trial (CARET) [37] and the Physicians' Health Study [38], supplementation with β-carotene had no effect on PCa incidence. Selenium and Vitamin E Cancer Prevention Trial (SELECT), an intergroup phase III, randomized, double-blind, placebo-controlled, population-based trial, showed that selenium and vitamin E may prevent the development or progression of PCa [39]. Clinical studies

3. Molecular links between aging and oxidative stress in prostate cancer Several molecular factors are known to be related either to aging or to oxidative stress in PCa. 3.1. p53

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and p53 tumour suppressor genes in prostate cancer, supported a model for cooperative tumour suppression in which p53 is an essential failsafe protein of PTEN-deficient tumours. In fact, combined deletion of these two tumour suppressor genes in murine prostate epithelium leads to the development of lethal prostate tumours [41]. Progression from early, PTEN-deficient prostate lesions to advanced prostate cancer in vivo requires loss of p53 function [49]. 3.2. Sexual hormones It is well established that normal serum androgen levels can promote ROS production and accumulation in prostate cancer cells. Androgen regulation of redox homeostasis is involved in a highly ordered signal transduction network of multimeric redox-sensitive transcription factors, enzymes and epigenetic modifications. In addition, overproduction of H2O2 plays a major role in androgenindependent cell proliferation and migration of LNCaP cells. Therefore, androgen-induced increase in ROS levels in prostate epithelial cells plays a key role in prostate cancer occurrence, recurrence and progression [50]. There is currently a debate about the theoretical association between testosterone replacement therapy and the initiation, progression, and aggressiveness of PCa [51,52]. A causal relationship between androgenic hormones and human prostatic carcinogenesis is plausible because PCa develops from an androgen-dependent epithelium and is usually androgen-sensitive at an early stage of the disease. It is known, and permanently cited as an argument for androgen deprivation, that cancer of the prostate is not observed in eunuchs and that total androgen suppression by castration (surgical or chemical) is a first line treatment for advanced PCa, when the tumour is still androgen-dependent. However, metastatic human prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and sustain intratumoural androgens at concentrations capable of activating AR target genes and maintaining tumour cell survival [53]. Androgen receptor (AR) is up-regulated in an age-associated manner in man and promotes continued proliferation and differentiation of the prostate [54]. In addition to changes in sex steroid hormone receptor expression and function that permit aberrant activation by weak steroid hormones, disease-associated alterations in steroid hormone intracellular signalling may also be mediated via changes in receptor coregulators [55,56] and/or by modulating the expression of hormone receptor target genes [57].A substantial role in altering both risk of recurrence/progression and prostate-specific cancer mortality can be attributed to megalin, an endocytic receptor expressed by prostate epithelial cells. This receptor can internalize biologically active androgens bound to sex hormone binding globulin and influence levels of steroid hormone uptake [58]. Because of the existence of many androgen- and oestrogen-responsive genes, age-associated changes in sex steroid hormones potentially affect numerous cellular pathways [59]. It has been shown that the decrease in testosterone production during aging is concomitant with an increase in prostate tumour growth (benign and malign) and that low level of testosterone or intraprostatic dihyrotestosterone level is associated with more aggressive cancer [60]. However, the most extensive analysis of all available epidemiological data found no evidence of a connection between sex steroids and carcinoma of the prostate [61]. The lower antioxidant capacity in testosterone-treated PCa cells increases their susceptibility to oxidative stress conditions [62,63]. The involvement of oxidative stress in an early event in PCa development was also suggested by Miyake et al. [64] who showed that androgen suppression is capable of decreasing oxidative stress. Therefore it was proposed that androgen withdrawal therapy combined with antioxidant agents may inhibit the progression of PCa [64].

3.3. Growth factors Prostatic cell homeostasis is maintained by an androgen-controlled balance of the transforming growth factor-β (TGF-β) and mitogenic cytokines, such as epidermal growth factor (EGF), fibroblast growth factor (FGF) and stem cell factor (SCF) [65]. Prostatic epithelial cells undergoing malignant transformation show the loss of expression of functional TGF-β receptors and overproduction of TGF-β. Loss of expression of functional TGF-β receptors provides a growth advantage to cancer cells whereas overproduction of TGF-β promotes extracellular matrix production, induces angiogenesis, and inhibits host immune function. The biological consequence of these activities is an enhanced tumourigenicity in prostate cancer [66]. The TGF-β1 signalling cascade is down-regulated by AR, possibly by direct interactions [67]. The age-related decrease in androgen levels may lead to an increase in TGF-β levels and sensitises prostate cells to stimulatory signals that results in excessive cellular proliferation [68]. Although a direct link between prostate cancer, TGF-β and oxidative stress is still elusive, it has been shown that TGF-β induces NADPH oxidase activity which causes radical production in hepatic stellate cells and in rat hepatoma cells [69,70]. Disruption of the androgen–oestrogen equilibrium can stimulate changes in stromal-derived factors that, in turn, act on the prostatic epithelium, leading to reactivation of growth, hyperplasia and neoplastic transformation. The age-dependent loss of growth suppression is linked to increases in the expression of stromal-derived factor 1 [71]. The pro-apoptotic gene p53 is also involved in the development of reactive stroma. Initial up-regulation of p53 in stromal fibroblasts by tumour cells may subsequently select for an apoptosis-resistance subpopulation of fibroblasts lacking p53 that then induce tumour progression in adjacent epithelial cell populations [72]. The stromal insulin-like growth factor (IGF) axis, which acts in a paracrine manner on prostatic epithelial cells, is modulated by the action of androgens. Locally produced proliferative IGFs and antiproliferative IGF-binding proteins (IGFBPs) play key roles in normal and neoplastic prostate development [73]. Co-culture experiments demonstrate that IGF-I mediates tumour–stromal cell interactions of PCa to accelerate tumour growth [74]. IGFBP-3, the most abundant IGFBP, may promote the survival of androgen independent PCa cells in an androgen-depleted environment [75]. Senescent fibroblasts secrete factors that stimulate proliferation, differentiation and invasiveness of pre-malignant epithelial cells directly or indirectly [76]. Fisher et al. [77] showed that oxidative/osmotic stresses on tumour cells increase the shedding of proheparin-binding EGF, which is processed by proteins of the ADAM family. In prostate carcinogenesis there are concomitant inductions of ADAM9 [78] and ROS [79] that can induce expression of the ADAMs via p38 mitogen-activated protein kinase activation [77]. The induced ADAM proteins are responsible for release of processed heparin-binding EGF, which further promotes cancer cell growth and survival through an EGFR-dependent mechanism. A relationship between the elevation of ADAMs and the progression and metastasis of cancer cells has been shown [80]. ADAM9 has potent biological activities since it degrades specific extracellular matrix substrates, releases active growth factors, interacts with key regulatory factors, and appears in the invasion front of several tumour metastases. ADAM9 −/−, when crossed with transgenic mice bearing prostate carcinoma, exhibited reduced tumour growth and local invasion [81]. In living cells the perturbation of cellular redox homeostasis is normally counteracted by sensing/signalling mechanisms to turn on/ off endogenous antioxidant responses [82]. To reinforce the role of oxidative stress in the development and progression of PCa, it should also be mentioned that many tumours present increased expression of vascular endothelial growth factor (VEGF) [83], reported as a marker of progression in PCa [84], and that

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ROS, and more in particular H2O2, are suggested to play an important role in angiogenesis, since VEGF mRNA is up-regulated by H2O2 in a dose- and time-dependent manner [85]. Furthermore, H2O2-mediated angiogenic signalling has been implicated in the so-called angiogenic switch, which allows non-invasive and poorly vascularised tumours to become highly invasive and angiogenic through direct activation of the transcription factor hypoxia-inducible factor (HIF) [86]. Thrombin receptor PAR1, identified as an oncogene and involved in the invasive and metastatic processes of PCa [87], contributes to tumour growth by enhancing tumour cell proliferation and by inducing the expression of VEGF [87].

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production of these mitogens and prosurvival factors could exert important effects on preneoplastic lesions originally initiated by predisposing genetic variables, carcinogens, or chronic inflammation [76]. This local production also provides an explanation for the paradoxical age-associated increases in hormonally driven prostatic diseases in the age-associated declines in testosterone, since increases in mitogens from the aged stroma substitute for androgen loss. It was also shown that the damage resulting from the alterations in the hormonal milieu is mainly derived from stromal inflammatory lesions and from the up-regulation of epithelial cyclooxygenase 2 (COX2) suggesting that this enzyme plays a role in prostate cancer risk and carcinogenesis [94,95].

3.4. Microenvironment 3.5. Vitamin D Tumourigenesis can be regarded as a gradual process by which cells acquire cellular immortalization, increased angiogenesis and invasion/metastasis and the ability to survive and proliferate under stress, such as lack of nutrients and oxygen, attack by immune cells, lack of proper attachment to other cells or to the extracellular matrix, DNA damage, oncogenic signals, and aberrant metabolism [31]. Although secondary and tertiary events are necessary to driving neoplastic progression, age-related alterations in the tumour microenvironment provide necessary or sufficient influences that promote tumour cell invasion and metastasis. It is generally accepted that histologically similar tumours behave less aggressively in the aged population [88], therefore the association between aging and PCa might be regarded as a paradox. Examination of several tumours demonstrated significantly delayed and slower growth in the aged than in young mice. Proposed mechanisms have focused on agerelated reductions in cell proliferation, increased tumour cell apoptosis and decreased angiogenesis. It has been proposed that the less permissive environment of aged tissues is an adaptive response to the greater risk of cancer conferred by age-related and environmentally induced increased risk of genetic mutations [88,89]. On the other hand, Campisi [90] and Anisimov [91] have suggested that the microenvironment of aged animals can lead to tumour growth. Age-related influences on tumour biology have implications for both the growth and treatment of histologically similar cancers in the young and aged, although the connections between patient age, tumour vessel density, growth rate and clinical outcomes are still to be established. Reed et al. [88] showed robust growth and angiogenesis in the TRAMP-C2 tumours in the aged mice, whereas the B16/F10 melanoma cell line, a well-studied tumour that is highly representative of other tumours that grow slowly in aged mice, showed a significant lack of growth in the aged mice relative to the young mice. The fact that tumour characteristics can be the primary determinant of the influence of aging on tumour angiogenesis and growth seems to solve the apparent contradiction of PCa. Moreover, aging-related changes can influence stromal–epithelial interactions leading to an environment permissive for neoplastic growth. Indeed nontumourigenic prostate epithelial cells can become tumourigenic when co-cultured with fibroblasts obtained from regions near tumours. Inactivation of the TGF-β type II receptor gene in mouse fibroblasts resulted in intraepithelial neoplasia (PIN) in the prostate and invasive cancers of the forestomach [92], a finding that further supports the important role of stroma in the process of carcinogenesis. Although senescent and tumour-associated reactive fibroblasts differ in growth potential and morphology, they share the ability to stimulate the proliferation and invasive behaviour of initiated epithelial cells through direct contact or secreted factors. Krtolica et al. [93] showed the ability of senescent human fibroblasts to promote the growth and tumourigenesis of premalignant and malignant breast epithelial cells, providing a mechanistic link between stromal aging and carcinogenesis. The molecular signature of prostate fibroblast senescence includes a cohort of factors capable of influencing the survival and proliferation of adjacent prostate epithelium. The local

Vitamin D can act as a membrane antioxidant to inhibit ironinduced lipid peroxidation of brain liposomes.and has also been reported to reduce oxidative stress by upregulating antioxidant systems in rats [96]. The roles of 25(OH) Vitamin D3 in regulating ROS systems seem to be dependent on the cellular environment since pro-oxidative effects are usually found in PCa cells whereas antioxidant effects usually occur in nonmalignant human prostate epithelial cells [96]. Risk of PCa was reported to be increased by vitamin D deficiency [97]. Moreover, 25(OH) Vitamin D3 seems to be involved in the regulation of cell proliferation in prostate and its signals are frequently found downregulated during the late stages of cancer progression through overexpression of SNAIL or other unknown mechanisms [96]. Increased 24-hydroxylation may inactivate hormonal Vitamin D metabolites as shown in cancers with an oncogenic amplification of 24-hydroxylase gene. Moreover, aging is accompanied by increases in the activity of 24-hydroxylase, whereas 1α-hydroxylation decreases and it is possible that a high serum concentration of 25(OH)D3 could induce 24-hydroxylase expression in prostate. In the AIPC Study of Calcitriol Enhancing Taxotere (ASCENT) trial, a high-dose formulation of calcitriol appeared to significantly lengthen survival in comparison to standard therapy, yet a Phase III trial (ASCENT-2) of the same formulation proved excessively toxic. The recent Phase II trial of calcitriol in advanced disease at 32 µg per week (vs. 45 µg used in ASCENT-2) was associated with a PSA response in 8 of 26 patients (31%) [98,99]. Finally, it is possible that high dose vitamin D alone or in combination with other agents may be effective in primary prevention [98].Therefore, vitamin D might be beneficial for preventing the development of this agedependent diseases. 3.6. Changes in oxidative defence system Aging increases the intracellular oxidative stress since intracellular ROS scavenging decreases progressively over a lifetime [15,46]. Signalling through redox reactions can contribute to an increased proliferation and malignant transformation, xenobiotics and environmental insults, that increase free-radical production, are known to act as both initiators and promoters of carcinogenesis [100]. Expression of glutathione S-transferase (GST) is diminished or absent in nearly 100% of human PCas, and this absence is tightly related to hypermethylation of the GST promoter CpG island. Aberrant methylation of promoter CpG islands is associated with silencing of genes and age-dependent methylation of several genes has been proposed as a risk factor for sporadic cancer. In examining the extent of gene methylation in normal human prostate, an aberrant hypermethylation as a function of age has been found suggesting that such age-related methylation may precede and predispose to full-blown malignancy [101]. In prostate cancer cells an increased ROS generation, due to the activation of NAD(P)H oxidase (Nox) systems, is critical for the malignant phenotype [102]. By analyzing the redox state of two human prostate carcinoma cell lines, i.e. LNCaP and PC3, characterized

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by different degrees of aggressiveness, Chaiswing et al. [103] showed that the aggressive nature of PC3 cells may be related to the ability to grow in a pro-oxidant state since a greater antioxidant capacity allows a greater cell survival. They also suggested that therapeutic results with antioxidants/pro-oxidant compounds will depend on the specific cellular redox biochemistry of the cancer cell type that is the target of therapy. ROS have been implicated in prostate carcinogenesis since oxidative DNA repair may be defective in prostate tissue as a result of uncontrolled oxidative stress and increased oxidative DNA damage [104,105]. Bostwick et al. have reported low levels of SOD1, SOD2 and catalase in prostate cancer thereby implicating oxidative DNA damage in prostate carcinogenesis [106]. One of the major cellular antioxidant responses is mediated by the Erythroid 2p45 (NF-E2)-related factor 2 (Nrf2), a basic-region leucine zipper transcription factor, that controls transcriptional activation of its downstream target genes by binding to the antioxidant response element (ARE). Many antioxidant and phase II detoxifying genes, i.e. glutathione S-transferase (GST), NAD(P)H quinone oxidoreductase, γ-glutamylcysteine synthetase, and heme oxygenase 1, contain ARE in the promoter regions [107]. Frohlich et al. [108] showed that Nrf2 and members of the GSTµ family are extensively decreased in human prostate cancer and that the loss of Nrf2 initiates a detrimental cascade of reduced GST expression, elevated ROS levels and ultimately DNA damage associated with tumourigenesis. Based on these reports, decreased GST expression/ activity seems to represent the target of both aging and oxidative stress. However, it is to note that, according to recent studies, the Keap1-Nrf2 system has been shown to be ambivalent since the constitutive activation of Nrf2, due to mutations in the Keap1 gene, is characteristically observed in lung cancer cells, suggesting that induced expression of Nrf2 target genes favours the prevalence of cancer cells [109]. 3.7. Inflammation Aging is accompanied by a pro-inflammatory state expressed by the increasing levels of inflammatory cytokines, including interleukin6 (IL-6), tumour necrosis factor alpha (TNF-α) and interleukin-1β (IL1β). There is evidence from many experimental studies that IL-6, TNF-

α and IL-1β inhibit testosterone secretion by their influence on the central (hypothalamic-pituitary) and peripheral (testicular) components of the gonadal axis explaining the decrease in serum testosterone levels in the aged. On the other hand, several studies suggest that testosterone supplementation reduces inflammatory markers [51,76]. These results suggest a close relationship between the development of a pro-inflammatory state and the decline in testosterone levels, two trends that are often observed in aging men supporting the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia [76]. Chronic inflammation and oxidative stress caused by toxins, dietary fat consumption, or high level of androgen may be important etiologic factors in PCa by producing repeated tissue damage and post-translational DNA modifications [110–112]. It is accepted that regions of prostatic inflammation and macrophages and neutrophil infiltration will generate free radicals, such as nitric oxide and various ROS that can induce hyperplastic or precancerous transformation [113]. 4. Aging, oxidative stress and prostate cancer Research in the MEDLINE database shows few reports directly linking aging to oxidative stress and to PCa. The first paper by Ripple et al. [114] dealt with the hypothesis that androgen exposure, known to be associated with the development of PCa, may alter the prooxidant– antioxidant balance of prostate cells. The hypothesis was based on the observation that PCa is associated with aging and that increasing age is associated, in many tissues, with a shift toward an increased oxidative stress. Physiological levels of androgens were shown to be capable of altering intracellular glutathione levels and increasing oxidative stress in androgen-responsive LNCaP prostate carcinoma cells, supporting the proposed hypothesis. Androgens, besides being responsible for a greater oxidative state in the prostate, also drive prostate morphogenesis. Recently, Prins et al. [115] reported that also oestrogens have a permanent influence on prostatic development and showed permanent alterations in prostate morphology and function caused by high oestrogenic exposures during the critical developmental period. In fact, early exposure to high doses of oestradiol results in an increased incidence of prostatic lesions with aging, i.e.

Scheme 2. Existing links between aging, oxidative stress and PCa. Aging decreases Vitamin D, p53 efficiency, antioxidant gene expression and androgen levels while increases inflammation. Each factor, directly or indirectly, enhances ROS production that, in turn, leads to prostate neoplastic treansformation. Antioxidant oral formulations oppose to ROS effects (red lines).

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hyperplasia, inflammatory cell infiltration and PIN, considered as the precursor lesions for prostatic adenocarcinoma. Furthermore, lowdose oestradiol exposures during development as well as exposures to environmentally relevant doses of the endocrine disruptor bisphenol A, followed by additional adult exposure to oestradiol, showed increased susceptibility to PIN lesions with aging. Gene methylation analysis revealed a potential epigenetic basis for the oestrogen imprinting of the prostate gland. They concluded that a full range of oestrogenic exposures during the postnatal critical period may result in an increased incidence and susceptibility to neoplastic transformation of the prostate gland in the aging male and may provide a foetal basis for this adult disease. However, the Authors did not investigate a direct correlation with oxidative stress. Nevertheless, the aging prostate shows changes in gene expression, i.e. up-regulation of HSP70 and HO-1, anti-apoptotic stress response genes preposed to avoid cellular damage [116]. Malignant and aging benign prostatic tissues show significantly increased proportions of 8-hydroxyadenine, and 8-hydroxyguanine, known as mutagenic oxidatively induced DNA base lesions [117]. The potential associations between gene variants that result in reduced neutralization of ROS and PCa risk was evaluated in CARET cohort [118,119]. Although variants in Mn-SOD, catalase (CAT), or glutathione peroxidase 1 (GPX1) seem to have no influence on PCa risk, the CAT (T/T) genotype was detected in men before age 65, suggesting that the phenotype is associated with a higher risk. In contrast with these findings, results from ATBC Study, that examined the role of MnSOD in the development of PCa, showed an effect of the MnSOD ala/ala genotype on the development of PCa, DNA damage, and immunosenescence, but not in the age associated mortality [120,121]. Based on the hypothesis that oxidative stress plays a major role in the aging process, Villeponteau et al. [122] identified oral formulations (YouthGuard, and Vi-Mix–Thiogen) that were maximally effective in decreasing oxidative stress therefore suggesting that human aging and the onset of many age-related diseases may be partly delayed by effective nutritional antioxidants and other supplements.

[23]

5. Conclusions

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While there is no generally agreed-on paradigm for the causes of aging, much evidence has accumulated in the last 20 years indicating that oxidative free radicals may play a significant role in both aging and in many of the age-related diseases Moreover, several data point to the fact that the process of aging causes spontaneous mutations in prostate cells and that PCa may theoretically result from an increase in oxidative stress, strictly related to aging. Therefore, based on the consideration that i) aging increases intracellular oxidative stress, ii) oxidative damage increases during aging, and iii) several molecular factors involved in PCa pathogenesis can be influenced/modulated either by oxidative stress or by aging, we conclude that a role for the aging-related oxidative stress in the neoplastic transformation of prostate cells can be plausibly suggested (Scheme 2). Acknowledgments The authors thank Mary Kerrigan (MA, Cantab) for valuable linguistic suggestions and Fondazione Cassa di Risparmio, Perugia for financial support. References

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