Prostate cancer is the leading non-cutaneous malignancy affecting men in the United States. One in every six men will be affected by prostate cancer. Due to the high incidence of prostate cancer, there is a need to develop biomarkers capable of identifying tumors from benign prostatic lesions. miRNAs are small molecules that regulate protein translation and impact cellular integrity when dysregulated. It is widely thought that miRNAs have the potential to serve as biomarkers. This study utilizes a unique combinatorial analysis of miRNA dysregulation to identify key miRNAs involved in prostate tumor initiation, progression and metastasis. Numerous dysregulated miRNAs potentially influence cancer development. A unique bioinformatically driven, network based approach was used to rank potential miRNAs that drive tumor progression. This study showed that miRNAs preferentially regulate highly connected proteins and transcription factors that affect numerous downstream targets. Thus dysregulation of a single highly connected miRNA could severely impact homeostatic maintenance of the tissue. In combination with miRNA profiling of a cancer cell progression model, the utilization of laser captured microdissection was used to separate cancer specific microRNA portraits from background differences arising from stroma cells, lymphocytes, and remaining normal epithelial cells. Integration of miRNA profiles with information gathered using networks biology and targeted proteomics resulted in the identification of a key miRNA that affects prostate cancer development and may be useful as a novel biomarker for identification/ staging of prostate cancer. Human miR-125b was identified as a potential miRNA suppressor of tumor formation. Previous work has identified miR-125-b as the post-transcriptional regulator of the ErbB2/ ErbB3 growth factor receptor family. Loss of miR-125b drives up expression of ErbB2/ ErbB3 activating downstream PI3K/AKT and RAS oncogene pathways. The level of miR-125b decreases 3-5-fold between benign and tumor epithelium. Further, miR-125b decreases during the development of prostatic intraepithelial neoplasia, which is regarded as an early indicator of prostate cancer. Thus miR-125b may be an ideal marker of early changes indicative of cancer. Restoration of miR-125b into highly tumorigenic, metastatic cells reduces mobility and invasion of underlying tissues. Taken together these data show miR-125b is a tumor suppressor in the healthy prostate.

Introduction: Cancer-related fatigue is often described by patients as a lack of energy, mental or physical tiredness, diminished endurance, and prolonged recovery after activity. Etiologic mechanisms underlying CRF are not well understood. Methods: A literature review was conducted to examine studies that had investigated the association of mitochondrial dysfunction with fatigue. The major conclusion from this review was that alterations in energy metabolism may contribute to fatigue. Therefore, the dissertation study focused on laboratory techniques for measuring mitochondrial oxidative phosphorylation enzymes (complexes I-V) and a mitochondrial-specific oxidative stress marker (superoxide dismutase 2 [SOD2]). The primary aim of the dissertation research was to describe levels of biomarkers of mitochondrial function, fatigue, and health-related quality of life (HRQOL) before and at the completion of external beam radiation therapy (EBRT) in men with nonmetastatic prostate cancer (NM-PC). To achieve this aim a secondary analysis of a descriptive, longitudinal study was conducted (#10-NR-0128). Results: A total of n = 22 men with NM-PC were included in this study. There were significant increases in fatigue and a significant decrease HRQOL from baseline to the completion of EBRT. However, there was no significant change in the biomarkers of mitochondrial function from baseline to EBRT completion. Given the exploratory nature of the study, it was decided to further investigate the patient sample to understand the relationship of fatigue and mitochondrial function in a well-characterized fatigue phenotype. There was preliminary evidence to support the possibility of distinct patterns of mitochondrial enzyme levels between those with a high intensification of fatigue and those with a low intensification of fatigue during EBRT; however, these differences were not statistically significant. Discussion: To our knowledge, this is the first study to describe the relationship between mitochondrial enzymes and fatigue before and during EBRT in men with NM-PC. The most important preliminary finding from this study is the possibility that mitochondrial enzymes might be related to fatigue intensification during EBRT. Future studies will be critical to determine if these preliminary findings are replicable, and if so, whether there are potential therapeutic targets in individuals at highest risk for fatigue intensification during EBRT.

Our recent studies have shown that that erectile dysfunction (ED) drugs including Sildenafil (Viagra), Vardenafil (Levitra) and Tadalafil (Cialis) enhance killing of several types of cancer cells by anticancer drug, Doxorubicin (DOX). We observed increased cell death by apoptosis in response to the combined treatment with ED drugs and DOX. However, the mechanism of such enhancement of cell death by combined treatment of ED drugs and DOX is not fully understood. Nuclear factor-κB (NF-κB) is an oxidant-sensitive transcription factor that plays a critical role in the immediate-early activation of a multitude of genes that have been documented to play critical role in programmed cell death (apoptosis). NF-κB activation has been shown to block apoptosis and its inhibition improves existing anti-oncogenic therapy such as chemotherapy. In the present study, we tested the hypothesis whether combined treatment of prostate cancer cells, PC3, with Sildenafil plus DOX would attenuate the activation of NFκB by inhibiting translocation of the p65 and p50 subunits to the nucleus and by phosphorylation of cytosolic IκB In addition, we investigated the effect of DOX and DOX plus Sildenafil on the expression of BCL family of proteins which play critical role in apoptosis. We treated PC3 cells with 1.5 μM DOX with or without 10 µM Sildenafil for 6 hours and 72 hours. The nuclear translocation of p65 and p50 and expression of BCL family of proteins was determined by western blot analysis. Our results show that combined treatment of DOX and Sildenafil significantly reduced the nuclear translocation of p65 and p50 as compared with DOX alone (P < 0.05). This correlated with the significant reduction in the expression of Bcl-2, BclxL and phosphorylation of BAD. These data provide an important mechanism by which Sildenafil treatment augments the apoptotic potential of DOX in PC3 cancer cells.

The chemokine receptor CCR5 has been implicated in the pathogenesis of prostate cancer. A novel natural product, anibamine, was isolated and found to be a micromolar inhibitor of the receptor. Anibamine was used as a new anti-prostate cancer lead compound. To discover the pharmacophore, analogs of anibamine were designed using the “deconstruction-reconstruction-elaboration” approach and synthesized. The establishment of a stereoselective route to only one isomer was explored, to increase yield and eliminate elaborate purification procedures. Analogs were found to have anti-prostate cancer activity at levels higher than the parent compound. The molecular modeling studies of the deconstructed analogs indicate that due to the psuedo-symmetry of the parent compound, the binding conformation of the deconstructed analogs may not be very different from each other. All this information together may help identify a next generation lead compound for anti-prostate cancer treatment.

<p>The androgen receptor (AR) signaling axis is a well-established therapeutic target in prostate cancer, due to its central role in tumor maintenance and progression. Although patients respond initially to androgen deprivation therapies and AR antagonists, they invariably progress to a castration-resistant state. Consequently, there is an unmet need for agents that target the AR signaling axis in a unique manner. </p><p>Histone deacetylase (HDAC) inhibitors repress AR signaling and prostate cancer growth in cellular and xenograft models. However, HDAC inhibitors also induce epithelial to mesenchymal (EMT) and neuroendocrine differentiation, both of which are associated with prostate cancer progression and aggressiveness. Given that 18 different HDAC isoforms have been identified in humans, and non-selective or Class I (HDAC1, 2, 3, and 8) HDAC inhibitors have been used in most of these studies, the relative contribution of individual HDAC isoforms to AR transcriptional activity and prostate cancer pathophysiology remains to be elucidated. The overarching goals of this study were to (1) determine the role of individual Class I HDACs in AR transcriptional activity and prostate cancer growth, (2) identify selective HDAC inhibitors that have reduced adverse profiles to the treatment of prostate cancer, and (3) identify potential HDAC-interacting proteins that regulate AR target gene transcription and prostate cancer growth. </p><p>Using genetic knockdown studies and pharmacological inhibitors with isoform selectivity, we identified that HDAC3 was required for AR transcriptional activity and proliferation in cellular models of androgen-sensitive and castration-resistant prostate cancer (CRPC). Additionally, we found that RGFP966, an HDAC3-selective inhibitor, attenuated the growth of a xenograft model of CRPC. Furthermore, non-selective HDAC inhibitors induced EMT and neuroendocrine markers in prostate cancer cells, but RGFP966 treatment did not. These studies provide rationale for selective inhibition of HDAC3 for the treatment of CRPC, and could provide an explanation for the lack of success using non-selective HDAC inhibitors in clinical trials for prostate cancer.</p><p>We also assessed the role of REV-ERB alpha, an HDAC3-interacting protein, in the regulation of AR transcriptional activity and prostate cancer growth. Using siRNA knockdown studies, REV-ERB inhibitors, and overexpression studies, we concluded that REV-ERB alpha; was required for AR target gene induction and prostate cancer growth, including models of CRPC. These studies also provide rational for targeting REV-ERB alpha; for the treatment of CRPC.</p><p>Taken together, these studies identify two novel targets in the HDAC signaling axis for the treatment of prostate cancer: HDAC3 and REV-ERB alpha. Our studies provide greater insight into AR transcriptional regulation and prostate cancer pathophysiology.</p> / Dissertation

Many pathways dysregulated in prostate cancer are also involved in epithelial differentiation. To better understand prostate tumor initiation, we sought to investigate specific genes and mechanisms required for normal basal to luminal cell differentiation. Utilizing human prostate basal epithelial cells and an in vitro differentiation model, we tested the hypothesis that regulation of NOTCH3 by the p38 MAPK family (hereafter p38-MAPK), via MYC, is required for luminal differentiation. Inhibition (SB202190 and BIRB796) or knockdown of p38a (also known as MAPK14) and/or p38d (also known as MAPK13) prevented proper differentiation. Additionally, treatment with a gamma-secretase inhibitor (RO4929097) or knockdown of NOTCH1 and/or NOTCH3 greatly impaired differentiation and caused luminal cell death. Constitutive p38-MAPK activation through MKK6(CA) increased NOTCH3 (but not NOTCH1) mRNA and protein levels, which was diminished upon MYC inhibition (10058-F4 and JQ1) or knockdown. Furthermore, we validated two NOTCH3 enhancer elements through a combination of enhancer (e) RNA detection (BruUV-seq) and luciferase reporter assays. Finally, we found that the NOTCH3 mRNA half-life increased during differentiation or upon acute p38-MAPK activation. These results reveal a new connection between p38-MAPK, MYC and NOTCH signaling, demonstrate two mechanisms of NOTCH3 regulation and provide evidence for NOTCH3 involvement in prostate luminal cell differentiation.

Background: African Americans have disproportionately higher burden of prostate cancer compared to European Americans. However, the cause of prostate cancer disparities is still unclear. Several roles have been proposed for calcium and vitamin D in prostate cancer pathogenesis and progression, but epidemiologic studies have been conducted mainly in European descent populations. Here we investigated the association of calcium and vitamin D intake with prostate cancer in multiethnic samples. Methods: A total of 1,657 prostate cancer patients who underwent screening and healthy controls (888 African Americans, 620 European Americans, 111 Hispanic Americans, and 38 others) from Chicago, IL and Washington, D.C. were included in this study. Calcium and vitamin D intake were evaluated using food frequency questionnaire. We performed unconditional logistic regression analyses adjusting for relevant variables. Results: In the pooled data set, high calcium intake was significantly associated with higher odds for aggressive prostate cancer (ORQuartile (1 vs. Quartile) (4) = 1.98, 95% C.I.: 1.01-3.91), while high vitamin D intake was associated with lower odds of aggressive prostate cancer (ORQuartile 1 vs. Quartile (4) = 0.38, 95% C.I.: 0.18-0.79). In African Americans, the association between high calcium intake and aggressive prostate cancer was statistically significant (ORQuartile 1 vs. Quartile 4 = 4.28, 95% C.I.: 1.70-10.80). We also observed a strong inverse association between total vitamin D intake and prostate cancer in African Americans (ORQuartile 1 vs. Quartile 4 = 0.06, 95% C.I.: 0.02-0.54). In European Americas, we did not observe any significant associations between either calcium or vitamin D intake and prostate cancer. In analyses stratifying participants based on Body Mass Index (BMI), we observed a strong positive association between calcium and aggressive prostate cancer and a strong inverse association between vitamin D intake and aggressive prostate cancer among men with low BMI (<27.8 kg/m(2)), but not among men with high BMI (>= 27.8 kg/m(2)). Interactions of race and BMI with vitamin D intake were significant (P-Interaction < 0.05). Conclusion: Calcium intake was positively associated with aggressive prostate cancer, while vitamin D intake exhibited an inverse relationship. However, these associations varied by race/ethnicity and BMI. The findings from this study may help develop better prostate cancer prevention and management strategies.

Upplevelsen av livskvalitet hos män med prostatacancer – en litteraturstudie                                         Abstrakt Bakgrund: Prostatacancer är den vanligast förekommande cancerformen bland män i Sverige. Många män lever med biverkningar efter behandlingen, vilket kan påverka deras liv negativt och hur de upplever sin livskvalitet. Syfte: Syftet var att belysa upplevelsen av livskvalitet hos män med prostatacancer. Metod: En litteraturstudie där åtta vetenskapliga artiklar med kvalitativ ansats har granskats, sammanställts och analyserats. Resultat: Tre huvudkategorier med sex kategorier identifierades: Bemästrande av situationen – Strävan efter väbefinnande genom kontroll, Insikt i sjukdomens påverkan. Adaption till livssituation – En förändringsprocess i livet, En kamp för sinnesro. Manlig identitet – Den förändrade sexualiteten påverkar identiteten, Relationer som stöd.   Konklusion: Upplevelsen av livskvalitet varierar från individ till individ och påverkas av bl.a. biverkningar efter behandling och synen på sin livssituation. Författarna tror att litteraturstudien kan medvetandegöra sjuksköterskor om vilken påverkan prostatacancer har på männens livskvalitet. Genom att ställa personliga frågor kan sjuksköterskan ge god vård utifrån varje persons individuella behov.   Nyckelord: Prostatacancer, livskvalitet, män, anpassning / The experience of quality of life in men with prostate cancer – A literature study   Abstract Background: Prostate cancer is the most common cancer among men in Sweden. Many men live with treatment related side effects which can cause a negative effect on their lives and the experience of their quality of life. Aim: The aim was to illuminate the experience of the quality of life in men with prostate cancer. Method: A literature study of eight articles with qualitative approach. The articles result have been reviewed, compiled and analyzed. Results: Three main categories and six categories were identified: Control of the situation – quest for wellbeing through control, insight in the impact of the disease. Adaptation to life situation – a reconstruction of life, a struggle for peace of mind. Male identity – the altered sexuality affects the identity, the support of relationships. Conclusion: The experience of quality of life varies between individuals and is affected by side effects after treatment and the way they are looking at their life situation. The authors believe that this literature study can raise awareness among nurses regarding the impact prostate cancer has on men’s quality of life. By asking personal questions the nurse can provide good nursing care based on each person’s individual need.   Keywords: Prostate cancer, quality of life, men, adaptation

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Orientador: Luis Antonio Justulin Junior / Resumo: A próstata é uma glândula acessória do sistema genital masculino e, além da dependência androgênica para o seu desenvolvimento e homeostasia, é influenciada por hormônios não esteróides, entre eles a prolactina (PRL). Estudos em modelos animais demonstraram que a PRL pode atuar com efeito anabólico sobre a glândula prostática. Assim, nosso objetivo foi investigar os efeitos da modulação de PRL sobre o desenvolvimento e maturação da próstata ventral (PV) de ratos. Foram utilizados ratos machos Sprague Dawley (DPN 90) divididos em 6 grupos (n=6): Grupo controle (CT): receberam solução salina; Prolactina (PRL): Prolactina (0,3mg/kg); Bromocriptiona (BR): inibidor de PRL (0,4mg/kg). Todos os animais foram submetidos diariamente (via subcutânea) do dia pós-natal 12 (DPN12) até os DPN 21 ou 35. Os animais foram anestesiados, pesados e posteriormente foram eutanasiados. O sangue e os lobos da PV foram coletados, pesados e processados para análises morfológicas, de western blot (WB) e RT qPCR. O tratamento com PRL induziu aumento de peso corpóreo dos animais no DPN35 comparado aos outros grupos. Histologicamente houve maior acumulo de screção no lúmen e diminuição do compartimento epitelial nos grupos PRL e BR comparados ao CT no DPN35. A reação imunohistoquímica para Ki67 demonstrou aumento de células proliferativas nos grupos tratados com PRL. A quantificação de PCNA confirmou estes dados, com aumento significante no grupo PRL35. A intensidade de reação imunohistoquímica para AR fo... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre