Mini-reviewOxidative stress in prostate cancer
Introduction
Prostate cancer is the most frequently diagnosed non-cutaneous malignancy in males, statistics from the American Cancer Society project 186,000 new cases and 28,000 deaths in US for the year 2008 [1]. This is a multi-focal, field-type disease which forms solid tumors of glandular origin. Androgens play an important role in the differentiation, development and normal functioning of the prostate and therefore likely have a role in developing prostate carcinogenesis. Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is no cure once the disease has spread beyond the prostate. Traditionally, treatment of prostate cancer was based on the deprivation of androgens to the developing tumor [2]. Though initially successful, this form of therapy fails in advanced stages of the disease, as the cells develop the ability to sustain growth and proliferation even in the absence of androgens, thus acquiring androgen independence [3]. Although several molecular alterations are known to be involved in the acquisition of androgen independence, the precise mechanism of this phenomenon is poorly understood. Molecular genetic changes in androgen independent prostate cancer cells result in a shift from paracrine to autocrine regulation driven by growth factor and cytokines [4], [5], [6].
Prostate cancer cells that proliferate in the absence of androgens typically have an aggressive phenotype. Though multiple factors and signaling pathways have been implicated in the development of aggressive prostate cancer [7], [8], the trigger for initiation of malignancy is still a topic of debate. Prostate cancer is mainly a disease of aging, with most cases occurring in men over the age of 55. Therefore, progressive inherent or acquired changes in cellular metabolism occurring over the years may play a very important role in the development of this disease. Many factors like diet, environmental carcinogens, and other inflammatory diseases have been linked to an increased risk of prostate cancer.
Hydroxyl radicals, peroxides and superoxides are ROS that are generated during everyday metabolic processes in a normal cell. ROS, generated either endogenously (mitochondria, metabolic process, inflammation etc.) or from external sources [9], play a vital role in regulating several biologic phenomena. While increased ROS generation has traditionally been associated with tissue injury or DNA damage which are general manifestations of pathological conditions associated with infection, aging, mitochondrial DNA mutations and cellular proliferation; new and exciting information points to an essential role for increased ROS generation in several cellular processes associated with neoplastic transformation and aberrant growth and proliferation [10], [11]. Processes associated with proliferation, apoptosis, and senescence may be a result of the activation of signaling pathways in response to intracellular changes in ROS levels [12]. Thus, excessive production of ROS or inadequacy in a normal cell’s antioxidant defense system (or both) can cause the cell to experience oxidative stress and the increased ROS may play a broader role in cellular processes associated with initiation and development of many cancers including prostate cancer.
Over the last decade association between prostate cancer risk and oxidative stress has been recognized, and epidemiological, experimental and clinical studies have unequivocally proven a role for oxidative stress in the development and progression of this disease. Differences in prostate cancer incidence among various races, environment, diet, life style, genetic constitution and hormone of an individual/community are some of the contributing risk factors for occurrence of prostate cancer [13], [14], [15]. Though recent studies have indicated that oxidative stress is higher in the epithelium of prostate cancer patients than men without the disease, the association of ROS-mediated oxidative stress and prostate cancer risk remains to be elucidated. Theories abound regarding their role in initiation of prostate cancer, and include but are not limited to, failure of antioxidant defense mechanism (due to persistent oxidative stress that leads to inherited and acquired defects in the defense system), mtDNA mutations, chronic inflammation, defective DNA repair mechanism and apoptosis etc., finally leading to the development of prostate cancer. Thus, many of the factors that are associated with prostate cancer like aging, imbalance of androgens, antioxidant system, dietary fat, and pre malignant conditions like high grade prostate intraepithelial neoplasia etc. may be linked to oxidative stress. In recent years several antioxidant trails have been conducted against prostate cancer, but the usefulness of such therapies needs extensive research before put into practice [16].
In this article, we reviewed literature pertaining to the role of ROS generation in prostate cancer, and the cellular effects of oxidative stress (Fig. 1). In addition, we will also discuss the relationship between prostate cancer susceptibility and oxidative stress in relation to antioxidant defense system, metabolic switch, mtDNA mutation, inflammation and regulation of androgens. This review is aimed at providing an overview about the role of ROS in promoting prostate cancer.
Section snippets
Antioxidant therapy in prostate cancer: where are we?
In 1981, a landmark study by Doll and Peto estimated that a higher percentage of cancer deaths in USA could be attributed to dietary factors, and proposed that antioxidant present in diet could deactivate formation of free radicals inside the cell [17]. After this discovery, a set of projects on cancer prevention were funded by NCI on a large scale, including clinical trials to test the role of dietary antioxidants in cancer prevention. Among the available antioxidant vitamins, vitamin E was of
Role of antioxidants in prostate cancer
Prostate cancer is commonly associated with a shift in the antioxidant–prooxidant balance towards increased oxidative stress. Previous studies highlighted the altered prooxidant–antioxidant status in prostatic tissue of man, rat and also in cell lines, where the imbalance between these antagonist played a major role in the initiation of prostate carcinogenesis [23]. However, there is very little idea about the cause of this imbalance. Androgens are considered to be the most powerful candidates
Metabolic switch and mitochondrial DNA mutations in prostate cancer
Mitochondrial DNA mutations are very frequent in cancer, and the accompanying mitochondrial dysfunction and altered metabolism may contribute to tumor pathogenesis and metastasis [30], [31], [32]. In the case of a normal prostate, higher concentration of zinc present in the tissue causes a block in Krebs cycle and accumulation of citrate in the prostatic fluid. Thus, normal prostate glandular epithelial cells have low respiration causing low terminal oxidation, are energy inefficient and
NADPH oxidase: an emerging candidate in prostate cancer
The NAD(P)H dependent reduction of molecular oxygen is responsible for the generation of ROS in a cell, in the form of superoxide anion (), which is then dismutaed to form peroxide (H2O2) [42]. Phagocytic cells generate higher amount of ROS using NADPH oxidases (Nox, Fig. 3) as part of their armory of microbicidal mechanisms. Recent reports also indicate their presence in some of the non-phagocytic tissue like fetal kidney, thyroid, prostate, colon etc. [43], [44]. NAD(P)H oxidase is
Aging, oxidative stress and prostate cancer
Aging is associated with many metabolic disorders and also with increased incidence of various cancers [50], [51]. Prostate cancer is a major age related malignancy with most incidences occurring between 54 and 75 years and rapid onset after 45 years [52], [53]. Many theories have been formulated to explain the molecular and biochemical aspect of aging, but Harman proposed “free radical theory of aging” in which he suggested that accumulation of damage to biomolecules caused by free radicals
Hypoxia and ROS
Extensive cell proliferation coupled with unorganized vasculature present in a tumor result in a low oxygen environment (hypoxia) forcing the cells to shift to anaerobic glycolysis for their energy requirements [81], [82]. Tumor cells have the ability to overcome low oxygen tension due to concomitant activation and stabilization of hypoxia inducible factor (HIF-1). Studies in many systems have shown an increase in intracellular ROS production when exposed to hypoxic environment [83] and mostly
Bacterial and non-bacterial prostatitis
Prostatitis is a manifestation characterized by painful inflammation of the prostate. Even though the reason for the occurrence of prostatitis is much in debate, two classes of prostatitis have been recognized, Bacterial and non-bacterial prostatitis [90]. Prostatitis is often associated with symptoms that range from voiding discomfort to adverse sexual function [91]. Epidemiological studies suggest that on an average about 11–16% of men in the United States have been or are diagnosed with
Summary and future directions
Evidence from epidemiological, experimental and clinical studies suggest that prostate cancer cells are exposed to increased oxidative stress. Environmental factors like diet, inflammation, and changes in cellular functions pertaining to NAD(P)H oxidase, androgen signaling, mtDNA mutations, aging, and redox imbalance are possible mechanisms that contribute to increased ROS generation (Fig. 1). This increased ROS may further stimulate cell proliferation, cause somatic DNA mutations and promote
Conflicts of interest statement
None declared.
Acknowledgements
Supported in part by NIH/NCI-P20 CA103680-Schwartz/Byers Program PI’s (H Koul, Pilot-Project PI), University of Colorado Cancer Center and Department of Surgery-School of Medicine Academic Enrichment Funds (H Koul).
References (113)
The biology of hormone refractory prostate cancer. Why does it develop?
Urol. Clin. North Am.
(1999)Mechanisms of prostate cancer progression to androgen independence
Best Pract. Res. Clin. Endocrinol. Metab.
(2008)- et al.
ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage
DNA Repair
(2002) Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy
Free Radic. Biol. Med.
(2007)- et al.
Cancer of the prostate: a nutritional disease?
Urology
(1997) - et al.
Androgenic regulation of oxidative stress in the rat prostate: involvement of NAD(P)H oxidases and antioxidant defense machinery during prostatic involution and regrowth
Am. J. Pathol.
(2003) - et al.
Functional characterization of transcription regulators that interact with the electrophile response element
Biochem. Biophys. Res. Commun.
(2001) - et al.
Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism of prostate epithelial cells
J. Biol. Chem.
(1997) Modulation of mitochondrial aconitase on the bioenergy of human prostate carcinoma cells
Mol. Genet. Metab.
(2004)- et al.
Accumulation of mitochondrial DNA deletions in the malignant prostate of patients of different ages
Exp. Gerontol.
(2001)
Evidence for a zinc uptake transporter in human prostate cancer cells which is regulated by prolactin and testosterone
J. Biol. Chem.
Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein)
J. Biol. Chem.
Curcumin and cancer: an “old-age” disease with an “age-old” solution
Cancer Lett.
mtDNA mutations in aging and apoptosis
Biochem. Biophys. Res. Commun.
An integrated theory of aging as the result of mitochondrial-DNA mutation in differentiated cells
Arch. Gerontol. Geriatr.
Proliferative disorders of the aging human prostate: involvement of protein hormones and their receptors
Exp. Gerontol.
Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and IGF-independent mechanism
J. Biol. Chem.
The development of human benign prostatic hyperplasia with age
J. Urol.
Growth factors and epithelial-stromal interactions in prostate cancer development
Int. Rev. Cytol.
Androgen manipulation alters oxidative DNA adduct levels in androgen-sensitive prostate cancer cells grown in vitro and in vivo
Cancer Lett.
Oxidative DNA damage in patients with prostate cancer and its response to treatment
J. Urol.
Dietary influences on endocrine-inflammatory interactions in prostate cancer development
Arch. Biochem. Biophys.
Hypoxia signalling controls metabolic demand
Curr. Opin. Cell Biol.
Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation
Cell Metab.
Reactive oxygen species-linked regulation of the multidrug resistance transporter P-glycoprotein in Nox-1 overexpressing prostate tumor spheroids
FEBS Lett.
Chronic bacterial prostatitis: an evolving clinical enigma
Urology
Prostatitis: what is the role of infection
Int. J. Antimicrob. Agents
Urologic diseases in America project, excessive antibiotic use in men with Prostatitis
Am. J. Med.
Oxidative DNA damage: assessment of the role in carcinogenesis, atherosclerosis, and acquired immunodeficiency syndrome
Free Radic. Biol. Med.
Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate
Cancer Res.
Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity
Cancer Res.
Molecular genetics of prostate cancer
Genes Dev.
Hormone resistance in prostate cancer
Cancer Metast. Rev.
Cross-talk between the androgen receptor and the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer
Curr. Cancer Drug Targets
Regulation of reactive oxygen species and genomic stability in hematopoietic stem cells
Antioxid. Redox. Signal.
Reactive oxygen species as intracellular messengers during cell growth and differentiation
Cell Physiol. Biochem.
Diet, androgens, oxidative stress and prostate cancer susceptibility
Cancer Metast. Rev.
Risk factors for prostate cancer
Ann. Int. Med.
The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today
J. Natl. Cancer Inst.
Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial
JAMA
Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial
JAMA
Diet, androgens, oxidative stress and prostate cancer susceptibility
Cancer Metast. Rev.
Supplemental and dietary vitamin E, β-carotene, and vitamin C intakes and prostate cancer risk
J. Natl. Cancer Inst.
Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial
J. Natl. Cancer Inst.
Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype
Cancer Res.
Prooxidant–antioxidant shift induced by androgen treatment of human prostate carcinoma cells
J. Natl. Cancer Inst.
Endocrine control of prostate cancer
Cancer Surv.
The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemo protection and drug resistance
Crit. Rev. Biochem. Mol. Biol.
The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis
Oncogene
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These authors contributed equally to this work.