Search

A 56-year-old woman with a 3-year history of hydrocephalus and ventriculo-peritoneal shunt placement, presented with worsening altered level of consciousness for 2 days. Imaging studies showed severe ventriculomegaly involving the lateral and third ventricles with multiple septated cysts noted in the lateral ventricles predominantly near the frontal horns. Histopathologic examination of the excised brain lesion revealed choroid plexus tissue and adjacent cerebral parenchyma with several non-caseating granulomas. Granulomatous inflammation was also identified in mediastinal lymph nodes. By using specific monoclonal antibodies, Propionibacterium acnes (P. acnes) were detected in non-caseating granulomas of both the brain and mediastinal lymph nodes. No acid-fast bacilli or fungal elements were present. To the best of our knowledge, this is the first demonstration of P. acnes in sarcoid granulomas of cerebral tissue, and it reinforces the possible link between P. acnes and sarcoidosis.

BACKGROUND. The peroxiredoxins (PRDXs) are emerging as regulators of antioxidant defense, apoptosis, and therapy resistance in cancer. Because their significance in prostate cancer (PCa) is unclear, we investigated their expression and clinical associations in PCa. METHODS. Transcript expression of PRDX1–6 in PCa was evaluated in cancer gene microarray datasets, whereas protein expression was evaluated by immunoblotting in prostate cell lines, and by immunohistochemistry (IHC) in prostate tissue microarrays (TMAs) containing tumor (n ¼ 80) and control (n ¼ 17) tissues. PRDX3 was also analyzed in TMAs containing PCa tissues from African-American and Caucasian patients (n ¼ 150 per group). PRDX expression was correlated with patients’ clinicopathologic characteristics. RESULTS. Analysis of PRDX expression in cancer microarray datasets revealed consistent upregulation (tumor vs. normal) of PRDX3 and 4. All PRDXs exhibited elevated protein expression in PCa cell lines, compared with non-tumor cells. IHC revealed significant overexpression of PRDX3 and 4 in PCa, associated with age, increased prostate specific antigen (PSA), tumor stage, or Gleason score. High PRDX3 staining was associated with early age and elevated Gleason score at time of radical prostatectomy in African-American but not in Caucasian patients with PCa. PSA recurrence free survival in patients with low PRDX3 tumor expression was significantly longer in Caucasians compared to African-Americans, but no difference was detected for high expression. CONCLUSIONS. PRDXs exhibit differential expression in prostate tumors, with PRDX3 and 4 consistently upregulated. Their role in PCa development, and their potential as biological determinants of PCa health disparities and novel therapeutic targets, deserve further investigation. Prostate 71: 755–765, 2011. # 2010 Wiley-Liss, Inc.

Prostate cancer (PCa) mortality is driven by highly aggressive tumors characterized by metastasis and resistance to therapy, and this aggressiveness is mediated by numerous factors, including activation of stress survival pathways in the pro-inflammatory tumor microenvironment. LEDGF/p75, also known as the DFS70 autoantigen, is a stress transcription co-activator implicated in cancer, HIV-AIDS, and autoimmunity. This protein is targeted by autoantibodies in certain subsets of patients with PCa and inflammatory conditions, as well as in some apparently healthy individuals. LEDGF/p75 is overexpressed in PCa and other cancers, and promotes resistance to chemotherapy-induced cell death via the transactivation of survival proteins. We report in this study that overexpression of LEDGF/p75 in PCa cells attenuates oxidative stress-induced necrosis but not staurosporine-induced apoptosis. This finding was consistent with the observation that while LEDGF/p75 was robustly cleaved in apoptotic cells into a p65 fragment that lacks stress survival activity, it remained relatively intact in necrotic cells. Overexpression of LEDGF/p75 in PCa cells led to the upregulation of transcript and protein levels of the thiol-oxidoreductase ERp57 (also known as GRP58 and PDIA3), whereas its depletion led to ERp57 transcript downregulation. Chromatin immunoprecipitation and transcription reporter assays showed LEDGF/p75 binding to and transactivating the ERp57 promoter, respectively. Immunohistochemical analysis revealed significantly elevated co-expression of these two proteins in clinical prostate tumor tissues. Our results suggest that LEDGF/p75 is not an inhibitor of apoptosis but rather an antagonist of oxidative stress-induced necrosis, and that its overexpression in PCa leads to ERp57 upregulation. These findings are of significance in clarifying the role of the LEDGF/p75 stress survival pathway in PCa.

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer related death in men in the US. PCa tumor aggressiveness, response to treatment, and mortality are worst in African-American men, compared to other ethnic groups, thus presenting a major health disparity. Our group reported previously that lens epithelium derived growth factor p75 (LEDGF/p75), a stress survival transcription coactivator, has elevated expression in PCa cells and tissues and promotes resistance to cell death induced by oxidative stress and chemotherapy. This is likely due to its ability to transactivate promoter regions of stress and antioxidant genes such as peroxiredoxin 6 (Prdx6) and heat shock protein 27 (HSP27). We hypothesized that high expression of LEDGF/p75 in prostate tumor cells and tissues contributes to the elevated expression of its putative target genes, some of which were identified in previous studies by our group and others. These include genes associated with stress protection and chemotherapy resistance such as HSP27, endoplasmic reticulum protein 57 (ERp57), and cytoglobin (CYGB). To test this hypothesis we performed an expression analysis of LEDGF/p75, HSP27, ERp57 and CYGB proteins in human PCa cell lines using immunoblotting, and in prostate tumor tissues using immunohistochemistry on tumor tissue microarrays (TMAs). PCa cell lines included stable PC3 clones overexpressing LEDGF/p75, as well as docetaxel (DTX) resistant PC3-DR and DU145-DR cells overexpressing this protein, with their corresponding parental DTX sensitive cell lines. The TMAs contained tissue specimens corresponding to prostate tumor, hyperplasia, normal-adjacent, and disease-free normal prostate tissues. Correlations between the expression of LEDGF/p75 and HSP27 or ERp57 or CYGB in cell lines as well as in tumors and normal tissues was determined. Our results indicated that overexpression of LEDGF/p75 in PC3 stable clones and in DTX resistant PCa cells was associated with increased protein expression of HSP27, ERp57 and CYGB. Statistically significant correlation was also observed between the protein levels of LEDGF/p75 and HSPp27 or ERp57 or CYGB in the TMAs. Luciferase-based transcription reporter assays confirmed that the promoter regions of HSP27 and ERp57 are activated by LEDGF/p75 in PCa cells. Chromatin immunoprecipitation assays also demonstrated binding of LEDGF/p75 to HSP27 promoter in PCa cells. Additional promoter activation studies are in progress to demonstrate that LEDGF/p75 transcriptionally regulates ERp57 and CYGB genes. These results enhance our understanding of the contribution of LEDGF/p75 overexpression to the activation of stress protective genes and its implications for chemotherapy resistance in metastatic PCa. Citation Format: Anamika Basu, Christina Cajigas, Benanette Medina, Heather Rojas, Hiya Banerjee, Melanie Mediavilla-Varela, Laisum Leoh, Carlos Casiano. Overexpression of the stress transcription co-activator LEDGF/p75 contributes to the upregulation of the stress protective genes HSP27, ERp57 and CYGB in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3117. doi:10.1158/1538-7445.AM2013-3117

Prostate cancer (PCa) is the most frequently diagnosed male cancer and the second leading cause of cancer death in men in the United States. This growing public health challenge is aggravated by disparities in the incidence and mortality of PCa among African-American (AA) men, compared to Caucasian (CC) men and other ethnic groups. The reasons for these disparities are not completely understood, although available evidence points to the convergence of multiple, interrelated factors, such as socioeconomics, unequal access to health care and screening, unhealthy lifestyle and diet, ancestry, and genetic susceptibility. Emerging evidence suggests that chronic inflammation of the prostate contributes to PCa development by inducing oxidative molecular damage, which in turns lead to the upregulation of stress and redox proteins that protect tumor cells against apoptosis and therapeutic interventions. Evaluation of the expression and role of these proteins in prostate tumors from different ethnic populations would help define molecular and cellular factors associated with prostate tumor aggressiveness and therapy resistance, and uncover potential biological determinants of PCa health disparities. The peroxiredoxin (PRDX) protein family consists of six anti-oxidant enzymes (PRDX1-6) that are emerging as key regulators of cellular anti-oxidant defense, and are being increasingly implicated in malignant transformation and therapy resistance. Very little is known about their role in prostate cancer. In this study we investigated their expression and association with clinical outcomes in prostate cancer (PCa). The expression of PRDX1-6 in PCa was evaluated in 14 cancer gene microarray datasets (from Oncomine and SPECS), by immunoblotting in a panel of 11 prostate cell lines, and by immunohistochemistry (IHC) in prostate tissue microarrays (TMA) containing tumor (n=80) and control (n=17) tissues. PRDX3 was also analyzed in TMA containing PCa tissues from AA and CC patients (n=150 per group). PRDX expression was correlated with patients’ clinicopathologic characteristics. Analysis of PRDX expression in cancer microarray databases revealed consistent upregulation (tumor vs normal) of PRDX3 and 4. All PRDXs exhibited elevated protein expression in PCa cell lines, compared with non-tumor cells. IHC revealed significant overexpression of PRDX3 and 4 in PCa, associated with increased prostate specific antigen (PSA), tumor stage, or Gleason score. High PRDX3 expression was associated with early age and elevated Gleason score at time of radical prostatectomy in AA but not in CC patients with PCa. PSA recurrence free survival in patients with low PRDX3 tumor expression was significantly longer in CC compared to AA patients, but no difference was detected for high expression. We conclude that PRDXs exhibit differential expression in prostate tumors, with PRDX3 and 4 consistently upregulated. The role of these two proteins in PCa development, and their potential as biological determinants of PCa health disparities and novel therapeutic targets, deserve further investigation. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A108.

Prostate Cancer (PCa) is the most frequently diagnosed male cancer and presents the greatest racial disparity of any cancer in the U.S., with high incidence and mortality among African American (AA) men. Eliminating these disparities requires a multi-prong approach that includes, in addition to aggressive social and public health interventions, a better understanding of the biology of prostate tumors from different ethnic groups, and the development of effective treatments for castration-resistant prostate cancer (CRPC). Our interest is to define the contribution of antioxidant and stress proteins induced by environmental factors to tumor aggressiveness and health disparities in PCa. We analyzed the expression of the peroxiredoxin (PRDX) protein family in prostate cell lines and prostate tissue microarrays (TMA), and observed a dramatic upregulation of PRDX3 in androgen responsive metastatic cell lines, particularly the AA-derived cell line MDA-PCa-2b. There was also a significant correlation between high PRDX3 tissue expression and PCa (when compared to normal tissues), advanced tumor stage, and elevated PSA (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2715.

Long-term cumulative exposure to environmental factors (i.e., dietary habits, unhealthy lifestyle, infectious agents, etc) lead to chronic inflammation and an augmented state of cellular oxidative stress, which contribute to the etiology and progression of various human cancers. We reported previously that lens epithelium derived growth factor p75 (LEDGF/p75), a transcription coactivator, has an elevated expression in human prostate tumors and cell lines. We hypothesize that LEDGF/p75 might be highly expressed in tissues with elevated oxidative stress such as tumors, because of its ability to transcriptionally activate stress genes that promote resistance to stress- and chemotherapy-induced cell death. To date, there have not been any comprehensive studies aimed at investigating the expression of LEDGF/p75 in human cancers. We performed an expression analysis of LEDGF/p75 protein in a panel of human cancers using immunohistochemistry on commercially available tissue microarrays (TMAs). Paraffin embedded tissue specimens were deparaffinized, rehydrated and stained with either a rabbit anti-LEDGF/p75 serum or the rabbit pre-immune serum as an antibody control, using a Biogenic i6000 auto stainer (Biogenex Corp.). Images were acquired using an Olympus BX50 microscope equipped with a Spot RT3TM camera. The TMA slides were assessed for LEDGF/p75 immunoreactivity by a pathologist who was blinded for the tumor/normal status of the tissues. A 4-tier grading system (0-negative, 1-weak, 2-moderate and 3-strong staining intensity) was used to evaluate the staining intensity. Associations between LEDGF/p75 expression in tumors and normal tissues were analyzed using Kruskall Wallis's rank sum test. We used TMAs (Imgenex and NDRI) containing specimens corresponding to over 20 major tumor types and normal adjacent tissues. Our data revealed high expression of this protein in tumors of prostate, pancreas, lungs, liver, thyroid, colon, breast and kidney, as compared to corresponding normal adjacent tissues. To further validate our findings, we analyzed LEDGF/p75 expression in the above-mentioned cancers using TMAs (US BIOMAX), each containing multiple tissues specimens of a specific major tumor type, as well as non-cancerous inflammatory disease and normal post-mortem control tissues. Immunohistochemical analysis revealed high expression of LEDGF/p75 in most of the tumor sections as compared to normal control tissues. The normal tissues showed minimal or no staining. The anti-LEDGF/p75 staining was mostly confined to the nucleus, although cytoplasmic staining was also evident in many cells. These results further validate the high expression of LEDGF/p75 in major human cancers and constitute the first step towards defining the biological significance of LEDGF/p75 expression in human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4667.