Carica papaya leaf extract inhibits prostatitis-associated prostatic hyperplasia via the TRAF6/TAK1/MEK/NF-κB pathway.

Prostatitis, defined as a pathological inflammatory change in the prostate tissue, is one of the most prevalent urological conditions in men. However, optimal management of prostatitis remains unclear, and treatment outcomes are unsatisfactory owing to adverse effects. Carica papaya leaf extract (PAL) is known for its antioxidant, immunomodulatory, and anticancer properties; however, evidence of its anti-inflammatory effect in prostatic tissues remains elusive. In this study, the therapeutic effects and underlying molecular mechanisms of PAL in mice with experimental autoimmune prostatitis (EAP) and a prostatic cell line (RWPE-1 cells) exposed to inflammatory conditioned medium were investigated. PAL suppressed pathological alterations in EAP and markedly reduced prostate weight in EAP mice. Histological analysis revealed that PAL alleviates prostatic hyperplasia. Furthermore, PAL significantly reduced cyclooxygenase-2 mRNA and protein expression; production of inflammatory cytokines, including interleukin-6, tumor necrosis factor-α, and transforming growth factor-ß; and TRAF6/TAK1/MEK/ERK and NF-κB pathway-related protein expression. TRAF6/TAK1/MEK/ERK and NF-κB pathway-related proteins were upregulated in inflammatory conditioned medium-stimulated RWPE-1 cells, but PAL reduced the expression of these markers. Particularly, PAL treatment suppressed the nuclear translocation of NF-κB p65 and phosphorylation of p65 in RWPE-1 cells exposed to the inflammatory conditioned medium. Collectively, the results demonstrate the anti-proliferative and anti-inflammatory effects of PAL in the experimental prostatitis model, which highlights the potential of PAL as a new therapeutic agent in the treatment of prostatic disease.

Tadalafil Alleviates LPS-Induced Inflammation and Oxidative Stress of RWPE-1 Cell by Regulating the Akt/Nrf2 Signaling Pathway.

Tadalafil (TAD) is primarily a treatment drug for erectile dysfunction. Studies have shown that TAD has a therapeutic effect on prostatitis, but the specific mechanism has not been reported. LPS induced RWPE-1 cells to form a model of chronic nonbacterial prostatitis (CNP). Cell activity was measured by MTT assay. Apoptosis was detected by TUNEL assay. Western blot was used to detect the expression of apoptosis-related proteins Bcl-2, Bax, Caspase-3, and cleaved caspase3. ELISA was used to detect the expression of inflammatory cytokines TNF-α, IL-6, and IL-8. GSH, catalase (CAT), and malondialdehyde (MDA) kits were used to detect the expression of oxidative stress-related indicators GSH, CAT, and MDA. Western blot was used to detect the expression of proteins related to Akt/Nrf2 signaling pathway. After different concentrations of TAD were given, the survival rate of LPS-induced RWPE-1 cells decreased, apoptosis increased, and inflammation and oxidative stress decreased. This process is accompanied by the activation of the Akt/Nrf2 signaling pathway. The addition of AKT inhibitor (HY-10249A) reversed the inhibitory effect of TAD on LPS-induced inflammatory response and oxidative stress of RWPE-1 cell. TAD alleviated LPS-induced inflammation and oxidative stress of RWPE-1 cell by regulating the Akt/Nrf2 signaling pathway.

Highlights on the Canine Prostatic Specific Esterase (CPSE): A diagnostic and screening tool in veterinary andrology.

In the last years, the need to look for an accurate and precise diagnosis of prostatic diseases in dogs has grown. Among other diagnostic tools, the seric CPSE has been studied and identified as a valid and specific biomarker for prostatic disorders, since it can result significantly more elevated in dogs affected by several prostatic abnormalities, such as benign prostatic hyperplasia, bacterial prostatitis and prostatic carcinoma. Therefore, dosing CPSE in serum represents a new diagnostic and screening tool. Dosing CPSE in everyday clinical practice has three objectives: (a) the diagnosis of benign prostatic hyperplasia; (b) the preventive screening of prostatic disorders in healthy dogs; (c) the medical follow-up in subjects with prostatic disorders during and after medical therapy. Neither circadian rhythms nor transrectal palpation performed during the andrological examination do affect CPSE. A sexual rest of at least 24 hr before dosing CPSE is recommended as it is affected by ejaculation.

Heme oxygenase levels and metaflammation in benign prostatic hyperplasia patients.

PURPOSE: To investigate the relationship between intra-prostatic levels of heme oxygenase (HO), metaflammation in benign prostatic hyperplasia (BPH) tissue in patients with MetS and moderate-severe lower urinary tract symptoms (LUTS). METHODS: Between January 2012 and June 2013, 132 consecutive patients, who underwent transurethral resection of the prostate for moderate-severe LUTS, secondary to clinical BPH, were enrolled. Prostate samples were investigated for the presence of an inflammatory infiltrate, according to the Irani score, and for HO-1 and HO-2 levels measurements. Patients were evaluated for the presence of metabolic syndrome (MetS) defined by the International Diabetes Federation. RESULTS: We observed that subjects with MetS exhibited greater Irani score (3.0 vs. 2.0; p < 0.05), Irani grade (2.0 vs. 1.0; p < 0.05) and lower value of HO-1 (4.55 vs. 6.01; p < 0.05) and HO-2 (0.81 vs. 2.66; p < 0.05). HO-1 (3.91 vs. 5.67; p < 0.05) and HO-2 (1.06 vs. 1.37; p < 0.05) were significantly reduced in patients with high intra-prostatic inflammation (Irani score ≥4). At the multivariate logistic regression analysis, HO-1 reduction (OR 0.588; p < 0.01), waist circumference (OR 1.09; p < 0.01), triglycerides (OR 1.013; p < 0.05) and HDL (OR 0.750; p < 0.05) were independent predictors of high intra-prostatic inflammation. We also found that HO-1 reduction (OR 0.598; p < 0.01) and the presence of MetS (OR 34.846; p < 0.01) were associated with Irani score ≥4. CONCLUSION: MetS-induced inflammation may play a key role in BPH. In detail, prostate metaflammation is inversely related to intra-prostatic HO-1 levels, serum HDL and positively with triglycerides.

Role of 5α-reductase inhibitors in benign prostatic diseases.

Testosterone is the most abundant androgen in serum. Intracellularly, testosterone is converted to dihydrotestosterone, the preferred ligand for androgen receptor transactivation, by the enzyme 5α-reductase. Three 5α-reductase isozymes have been discovered and they are expressed ubiquitously in human tissues. Testosterone and dihydrotestosterone have different but complimentary functions. Dihydrotestosterone has 2-5 times higher binding affinity for the androgen receptor than testosterone, and 10-fold higher potency of inducing androgen receptor signaling than testosterone. The role of dihydrotestosterone was discovered after the description of 5α-reductase type 2 deficiency in 1974, where affected males have normal internal but ambiguous external genitalia. Neither BPH nor prostate cancer has been reported in these patients. Currently, two 5α-reductase inhibitors are available for clinical use. This review will discuss the important clinical trials of 5α-reductase inhibitors in the treatment of benign prostatic diseases.

[Effects of geniposide on treating experimental chronic prostatitis rats].

OBJECTIVE: To study the effect of geniposide on treating experimental CP rats. METHOD: The animal model of CP was made with rats by injecting hemorrhoid injection. Rats in experiment group were randomly devided into model group, Qianliekang tablets group (2 g x kg(-1)) and geniposide high, middle, low dose groups (20, 10, 5 mg x kg(-1)). Subsequently, the state of all rats, prostate index, WBC and lecithine corpuscle, LDH5/LDH1, and prostatic histopathological changes were observed. Count of total cellular score (TCS) and quantitation of inflammatory cell, fibroblasts, glandular organ, calculation of glandular cavity area, and their changes of morphology were analyzed. RESULT: Compared with model group, the prostate index, WBC and LDHS/LDH1 of the rats in Qianliekang tablets group, high dose geniposide group and middle dose geniposide group were significantly decreased, while the quantities of lecithine corpuscle were remarkably increased (P < 0.01 or P < 0.05). Compared with model group, the number of inflammatory cells and fibroblasts in Qianliekang tablets group, high dose geniposide group were decreased, and the quantity of glandular organ and area of glandular cavity in these groups were increased (P < 0.05 or P < 0.01). CONCLUSION: Geniposide of high and middle dose can reduce leucocytes infiltration, restrain the hyperplasia of fibrous tissue, and recover the secretion function of prostate. It show that geniposide is significantly potential to cure rats which are exposed to chronic prostatitis.

[Xiaojin Wan inhibits the expression of COX-2 in prostate tissues of prostatitis pain rats].

OBJECTIVE: To study the effect of Xiaojin Wan on the expression of COX-2 in the prostate tissues of rats with prostatitis pain, and the action mechanism of the drug alleviating the prostatitis pain. METHODS: Sixty male Wistar rats were randomized into two groups, 10 as blank controls, injected with aqua pro injection into the ventral part of prostate, and the other 50 as prostatitis pain models, given complete Freund's adjuvant (CFA). Three days later, the pain model rats were again equally divided into 5 subgroups: model control, Celecoxib Capsules, high-, median- and low-dose Xiaojin Wan, receiving intragastric administration of distilled water, Celecoxib Capsules and different doses of Xiaojin Wan respectively for 4 weeks. Then they were killed, the harvested tissues fixed with 10% paraformaldehyde and the changes of the COX-2 expression in the prostate detected with the immunohistochemical technique and graphics video analysis system. RESULTS: The expression of COX-2 was strong in the model group, significantly lower in the high- and median-dose and the Celecoxib Capsules groups than in the model control (P < 0.01) as well as in the high-dose than in the median- and low-dose groups (P < 0.01). CONCLUSION: Xiaojin Wan may alleviate prostatitis pain by inhibiting the expression of COX-2 in prostate tissues.

Targeted overexpression of vav3 oncogene in prostatic epithelium induces nonbacterial prostatitis and prostate cancer.

Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor (AR), and stimulates growth in prostate cancer cells. The purpose of this study is to further determine the potential role of Vav3 in prostate cancer development in genetically engineered mouse model. We generated Vav3 transgenic mice by targeted overexpression of a constitutive active Vav3 in the prostatic epithelium. We found that overexpression of Vav3 led to development of mouse prostatic intraepithelial neoplasia and prostate cancer at the age of as early as 3 months. The AR signaling axis and phosphatidylinositol 3-kinase-Akt signaling were elevated in the prostate glands of Vav3 transgenic mice. In addition to prostate cancer, Vav3 transgenic mice developed significant nonbacterial chronic prostatitis in the prostate gland with notable infiltration of lymphomononuclear cells (monocytes, lymphocytes, and plasma cells), which was associated with elevated incidence of prostate cancer. DNA microarray and signaling pathway analysis revealed that the top diseases and disorders were inflammatory diseases and cancer of the prostate gland in Vav3 transgenic mice. In vitro analysis showed that overexpression of Vav3 in prostate cancer cells enhanced nuclear factor-kappaB (NF-kappaB) activity, implicating an underlying mechanism of innate inflammatory response induced by elevated Vav3 activity. These data showed that Vav3 overexpression in the prostate epithelium enhanced both the AR signaling axis and NF-kappaB-mediated pathway, which potentially contributed to the development of nonbacterial prostatitis and prostate cancer.

Intraprostatic botulinum toxin a injection inhibits cyclooxygenase-2 expression and suppresses prostatic pain on capsaicin induced prostatitis model in rat.

PURPOSE: Cyclooxygenase-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins, which are important mediators of inflammation and pain. We investigated the effect of intraprostatic botulinum toxin A administration on pain reaction and cyclooxygenase-2 expression in a capsaicin induced prostatitis model in rats. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were injected with vehicle or capsaicin (10 mM, 0.1 cc) into the prostate. The nociceptive effects of capsaicin were evaluated for 30 minutes using a behavior approach. The prostate and L6 spinal cord were then removed for histology and cyclooxygenase-2 expression using Western blotting or immunostaining. A second set of animals was injected with botulinum toxin A (5 to 20 U) into the prostate 1 week before intraprostatic injection of capsaicin. RESULTS: Capsaicin induced increased pain behavior and inflammatory reaction. Botulinum toxin A 1 week before treatment dose dependently decreased inflammatory cell accumulation, cyclooxygenase-2 expression and prostatic pain. Botulinum toxin A (20 U) significantly decreased inflammatory cell accumulation, and cyclooxygenase-2 expression in the prostate, ventral horn and dorsal horn of the L6 spinal cord (93.5%, 89.4%, 90.5% and 77.5%, respectively). It decreased pain behavior for eye and locomotion scores (59.5% and 40.0%, respectively). CONCLUSIONS: Intraprostatic capsaicin injection activates cyclooxygenase-2 expression in the prostate, and spinal sensory and motor neurons, and it induces prostatic pain. Botulinum toxin A pretreatment could inhibit capsaicin induced cyclooxygenase-2 expression from the peripheral organ to the L6 spinal cord and inhibit prostatic pain and inflammation. This finding suggests a potential clinical benefit of botulinum toxin A for the treatment of nonbacterial prostatitis.

[Intraprostatic urinary reflux associated prostatitis caused by partial urethral obstruction in the rat model].

OBJECTIVE: To investigate the pathogenesis of chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS) by constructing the rat model of intraprostatic urinary reflux associated prostatitis caused by partial urethral obstruction. METHODS: Fifty-four SD male rats were divided into an experiment group (n = 30) and a partial urethral obstruction (PUO) sham operation group (n = 24). Shinsuke Takechi's surgical method was adopted to achieve PUO and induce intraprostatic urinary reflux in the experiment group. While in the sham operation control group, the prostates were harvested at 1, 3 and 7 days after release from 3-day PUO, their morphological changes observed with the light microscope and the expression of cyclooxygenase-2 (COX-2) examined by immunohistochemistry. RESULTS: Inflammation was observed in the prostate of the experiment group at 1, 3 and 7 days after release from PUO and alleviated with the passing of time, while the control group remained normal. The expression of COX-2 in the prostate was significantly higher in the experiment group than in the control (P < 0.05) and the staining of COX-2 became stronger with the lapse of time (P < 0.05). CONCLUSION: An animal model of intraprostatic urinary reflux associated prostatitis was constructed. The up-regulated expression of COX-2 induced by intraprostatic urinary reflux may be closely related with the development of CP / CPPS.

Is it necessary to cure prostate cancer when it is possible? (Understanding the role of prostate inflammation resolution to prostate cancer evolution).

OBJECTIVE: Definitive therapy with radical prostatectomy, cryotherapy, or radiation therapy generally follows the initial diagnosis of prostate cancer, particularly when men have at least 10 additional years of life expectancy. There is growing concern regarding the optimal conservative treatment for patients who decline or do not otherwise qualify for such definitive curative treatment. For those patients who choose a watchful waiting approach, it would be beneficial to know what specific dietary and nutritional methods could potentially slow the progression of their disease. In this prospective study, it was our goal to analyze the efficacy and safety of treating prostate cancer conservatively using the principles of a Mediterranean diet in association with a specific prostate nutritional supplement. METHOD: Twenty-three men aged 43-74 (median age: 64) with biopsy proven, organ-confined prostate cancer who had already declined immediate hormonal therapy and attempts at a curative cancer treatment agreed to participate in a Chronic Disease Management (CDM) protocol highlighted by diet with a specific prostate nutritional supplement. The diet recommended was a modified Mediterranean diet while a patented nutritional prostatitis formula (Peenuts) was the supplement common to all patients. Prostate specific antigen (PSA), a recognized marker of prostate disease and prostate cancer activity, was the primary indicator to validate exacerbation or suppression of disease. All men were followed with serial PSA testing, a digital rectal exam, an International Prostate Symptom Score index (IPSS-Index) and an expressed prostatic secretion (EPS) examination. The primary Gleason sum/score represented in this study was 6 (n = 11), while Gleason sum patterns 5, 5/6, 6/7, and 7 were also evaluated. Referencing the Partin Tables, organ confinement was predicted to be 66%. RESULTS: Eighty-seven percent of men (n = 20) noted a 58% reduction (range of improvement: 13%-90%) in PSA over an average of 38.5 months (range: 13-84 months). The remaining 13% of men included three men who experienced a mild elevation in PSA of 0.3 ng/ml, 0.7 ng/ml, and 0.9 ng/ml over 14 months, 42 months, and 34 months, respectively. Fifteen men had completed an initial and secondary IPSS-Index while 14 men had undergone an initial and secondary EPS. The mean percentage reduction in IPSS-Index was 61% (range: 20%-100% with a median of 55%), while men evaluated with EPS examinations noted a mean percentage reduction in white blood cells of 77.5% (range: 33%-99% with a median of 82%). These results were evaluated using the t-test, Wilcoxon Analysis and the Null Hypothesis and found to be statistically significant. CONCLUSION: Clearly there is a need to develop effective alternative conservative therapies for the increasing numbers of prostate cancer patients who will not tolerate definitive curative measures or simply choose a conservative approach. Although this prospective study had no control arm, was of limited duration and included only 23 participants, it did appear to show significant benefit to the majority of prostate cancer patients treated with selective nutritional and dietary therapy alone. Such treatments may provide a safe and effective long-term treatment alternative for some patients. Further study is encouraged.

Tissue inhibitor of metalloproteinase-2 (TIMP-2) location in the ventral, lateral, dorsal and anterior lobes of rat prostate by immunohistochemistry.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a major role in extracellular matrix component degradation in several normal and abnormal tissue situations; they are also found in human seminal plasma. MMPs have been found in rat prostate secretions and are nearly lobe specific in expression pattern. The aim of this study was to evaluate whether TIMP-2, like other semen components, is expressed differently from different rat prostatic lobes. Immunohistochemical staining was performed in both young and adult rat ventral (VP), lateral (LP), dorsal (DP), and anterior (AP) prostatic lobes and confirmed by western blotting. TIMP-2 expression was found in the epithelial cells in the following sequence: LP>AP>DP>VP, in both young and adult rats. In this study, 100% of adult LP presented histological signs of prostatitis, where TIMP-2 immunostaining was positive in normal epithelium even with intraluminal neutrophils, but was reduced or absent in the epithelium with intraepithelial leukocytes or with periductal stroma disorganization associated with mononuclear cell infiltration. However, TIMP-2 expression in LP was not induced by prostatitis, since younger rat LPs were also strongly TIMP-2 positive. The distal and intermediate VP regions were TIMP-2 negative, but the proximal regions were strongly stained. Western blotting results confirmed the high TIMP-2 expression in the LP lobe. Thus, TIMP-2 is expressed differently between the prostatic lobes and is another nearly lobe-specific protein, which plays a role in the regulation of MMP activity in seminal plasma and glandular homeostasis. TIMP-2 is also another regional ductal variation of VP. Further studies should address whether TIMP-2 expression is related to the highest incidence of rat LP prostatitis and adenocarcinoma.

Manganese superoxide dismutase polymorphism in chronic pelvic pain syndrome patients.

Chronic pelvic pain syndrome (CPPS) is a common and serious health problem affecting the quality of life in men. In this study, we aim to investigate the manganese superoxide dismutase (MnSOD) polymorphism at nucleotide 47 as a result of the change of Ala to Val on the protein sequence in CPPS patients. The frequencies were 0.45 and 0.38 for the Ala and 0.55 and 0.62 for Val in National Institutes of Health category 3a and 3b groups. The differences between control and CPPS patients were statistically significant (P<0.05). However, frequencies recorded in 3a and 3b groups were not statistically different (P>0.05). Same results were obtained for enzyme analysis of MnSOD and glutathione peroxidase. Control group antioxidant enzyme levels were higher than patients' samples. The low antioxidant status of CPPS patients might be the clue for pathophysiological problems, and highly distributed Val allele frequency can be a mediator point of the illness. Our findings lead to the suggestion that oxidative disorder-linked medical health problems can be associated with genetic risk factors such as polymorphisms.

Aromatase and prostate cancer.

The normal growth and development of the prostate requires the presence and action of androgens, which are also known risk factors in the origins of benign and malignant prostate disease. Paradoxically, the incidence of prostate disease increases with age when serum androgen levels are in decline and emerging evidence suggests that estrogens may also be important in the normal prostate, as well as in the etiology of prostate disease. Both estrogen receptor subtypes are present in the prostate, demonstrating that the gland responds directly to estrogens. Recent data suggests that estrogens play a role in prostate disease and has demonstrated that high doses of estrogens induce premalignant dysplasia and in combination with high doses of androgens, malignancy. The production of estrogens from androgens is mediated by the aromatase enzyme, the aberrant expression of which plays a critical role in the disease process in other tissues, most notably the breast. The prostate expresses aromatase within the stroma of benign tissue, while in malignancy there is an induction of epithelial expression with altered promoter utilisation. Although the presence of aromatase in the prostate and its aberrant expression in prostate cancer is significant, its role and contribution to prostate carcinogenesis remains unclear. Transgenic mouse models lacking aromatase (ArKO) and over-expressing aromatase (AROM+) have provided an ideal means to examine aromatase expression in the prostate. Studies using these animals may lead to a better understanding of the role that aromatase--and therefore estrogen--plays in the development and progression of prostate disease.

Cyclooxygenase-2 and angiogenesis in prostate cancer.

Chronic inflammation has been associated with resulting in malignancies in prostate cancer patients. In the May 2005 issue of Clinical Cancer Research, a study by Wang et al. demonstrates a relationship between COX-2 expression and the local chronic inflammation within prostate cancer and the increased angiogenesis. Confirming the existence and extent of this relationship is essential in the determination of therapeutic modalities for the prevention and treatment of prostate cancer.

Matrix metalloproteinases in the pathogenesis of estradiol-induced nonbacterial prostatitis in the lateral prostate lobe of the Wistar rat.

Chronic nonbacterial prostatitis develops spontaneously with age in the lateral lobe of the prostate in some strains of rat. Our objective was to examine the role of matrix metalloproteinases (MMP) in the pathogenesis of chronic nonbacterial prostatitis using a chronic estrogen treatment, Wistar rat model (Prostate 12 (1988) 271). Male Wistar rats, 90 days of age (8 rats/group), were castrated and groups were implanted 8 days later with 1 cm silastic tubings containing estradiol 17 beta (E2). Some animals received 5-cm silastic tubings of dihydrotestosterone (DHT) or testosterone (T) on day 22 and all untreated control and experimental animals were sacrificed on day 36 of the protocol. MMP activities were determined by SDS-gelatin-, casein-, and carboxymethyl transferrin-polyacrylamide gel zymography. A light/mild interstitial monocytic infiltration was found in the ventral lobes, but not other lobes, of half of the untreated control rats. This ventral lobe interstitial inflammation was not affected by E2 treatment. A prominent to heavy inflammation, including both intraluminal neutrophil and interstitial monocytic infiltrates, was produced by E2 treatment at a 100% incidence in the lateral lobes. Prominent MMP activities were detected in the lateral lobes of E2-treated rats, including both the active (55 and 81 kDa) and proenzyme (72 and 92 kDa) forms of MMP-2 and MMP-9, respectively. These activities were strongly attenuated by treatment of E2-implanted animals with T, which also reduced inflammation; but they were only weakly affected by DHT given with E2, which did not reduce inflammation. Similarly, DHT treatment of E2-implanted castrated rats restored the wet weight of the lateral lobe, but it did not fully restore secretion volume production, whereas T treatment of estrogenized rats increased lateral lobe wet weight and secretion volume above that of untreated controls. E2 treatment also induced an activity in casein gels of about 27 kDa with properties of MMP-7; that is, molecular mass, inhibition by EDTA, stimulation by heparin sulfate in casein and carboxymethylated transferrin gels. A high molecular weight nonmetalloproteinase activity (>160 kDa) was detected in gelatin gels in the lateral prostate lobe of both treated and untreated control animals. In comparison to the lateral lobe, E2 treatment produced only minimal effects on MMP activities in the ventral and dorsal prostatic lobes. Thus, elevated MMP-2, MMP-7, and MMP-9 activities in lateral lobe prostatitis correlate with leukocyte infiltration in the inflammatory response. These proteinases may help mediate the accompanying epithelial atrophy and tissue damage in this organ.

The diet, prostate inflammation, and the development of prostate cancer.

Evidence that somatic inactivation of GSTP1, encoding the human pi-class glutathione S-transferase, may initiate prostatic carcinogenesis is reviewed along with epidemiological evidence implicating several environment and lifestyle factors, including the diet and sexually transmitted diseases, as prostate cancer risk factors. An integrated model is presented featuring GSTPI function as a 'caretaker' gene during the pathogenesis of prostate cancer, in which the early loss of GSTPI activity renders prostate cells vulnerable to genome damage associated with chronic prostatic inflammation and repeated exposure to carcinogens. The model predicts that the critical prostate carcinogens will be those that are substrates for GSTP1 detoxification and are associated with high prostate cancer risk diet and lifestyle habits.

X Chromosomal short tandem repeat polymorphisms near the phosphoglycerate kinase gene in men with chronic prostatitis.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) causes substantial morbidity afflicting approximately 10% of adult males. Treatment is often empirical and ineffective since the etiology is unknown. Other prostate and genitourinary diseases have genetic components suggesting that CP/CPPS may also be influenced by genetic predisposition. We recently reported a highly polymorphic short tandem repeat (STR) locus near the phosphoglycerate kinase gene within Xq11-13. Because this STR is in a region known to predispose towards other prostate diseases, we compared STR polymorphisms in 120 CP/CPPS patients and 300 control blood donors. Nine distinct allele sizes were detected, ranging from 8 to 15 repeats of the tetrameric STR plus a mutant allele (9.5) with a six base deletion in the flanking DNA sequence. The overall allele size distribution in the CP/CPPS patients differed from controls (Chi-square=19.252, df=8, P=0.0231). Frequencies of two specific alleles, 9.5 and 15, differed significantly in CP/CPPS vs. control subjects and allele 10 differed with marginal significance. Alleles 9.5 and 10 were both more common in CP/CPPS patients than controls while allele 15 was less common. These observations suggest that Xq11-13 may contain one or more genetic loci that predispose toward CP/CPPS. Further investigations involving family studies, larger patient populations, and other control groups may help elucidate this potential genetic predisposition in CP/CPPS.

Preneoplastic prostate lesions: an opportunity for prostate cancer prevention.

Environmental factors, especially the diet, play a prominent role in the epidemic of prostate cancer (PCA), in the United States. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, anti-oxidants, and various micronutrients, but the specific roles dietary agents play in promoting or preventing PCA remain controversial. We have collected evidence to suggest that GSTP1, the gene encoding the pi-class glutathione S-transferase (GST), may serve a "caretaker" function for prostatic cells. Although GSTP1 can be detected in normal prostatic epithelium, in almost all PCA cases, PCA cells fail to express GSTP1 polypeptides, and lack of GSTP1 expression most often appears to be the result of somatic "CpG island" DNA methylation changes. Loss of GSTP1 function also appears to be characteristic of prostatic epithelial neoplasia (PIN) lesions, thought to represent PCA precursors. We have recently learned that a new candidate early PCA precursor lesion, proliferative inflammatory atrophy (PIA), characterized by proliferating prostatic cells juxtaposed to inflammatory cells, contains epithelial cells that express high levels of GSTP1. These findings have formed the basis for a new model of prostatic carcinogenesis, in which prostatic cells in PIA lesions, subjected to a barrage of inflammatory oxidants, induce GSTP1 expression as a defense against oxidative genome damage. When cells with defective GSTP1 genes appear amongst the PIA cells, such cells become vulnerable to oxidants and electrophiles that inflict genome damage that tends to promote neoplastic transformation to PIN and PCA cells. Subsequently, PIN and PCA cells with defective GSTPI genes remain vulnerable to similar stresses tending to promote malignant progression. This new model for prostatic carcinogenesis has implications for the design of new prostate cancer prevention strategies. Rational prevention approaches might include: (i) restoration of GSTPI expression via treatment with inhibitors of CpG methylation, (ii) compensation for inadequate GSTPI activity via treatment with inducers of general GST activity, and (iii) abrogation of genome-damaging stresses via avoidance of exogenous carcinogens and/or reduction of endogenous carcinogenic (particularly oxidant) stresses.