bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C14: Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737
Authors: Song Jin H. , Kraft Andrew S. 
Published: May 2013

Abstract
Pim serine/threonine kinases contribute to prostate tumorigenesis and therapeutic resistance, yet Pim kinase inhibitors appear to have only limited effects on prostate cancer cell survival. Since overexpression of Bcl-2 family members are implicated in chemotherapeutic resistance in prostate cancer, we investigated the cooperative effects of Pim kinase inhibition with ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Pim inhibitors decreased levels of the Bcl-2 family member Mcl-1, both by blocking 5′- cap dependent translation and decreasing protein half life. Additionally, Pim inhibition transcriptionally increased levels of the BH3 protein Noxa by activating the unfolded protein response (UPR), lead to eIF-2α phosphorylation and increased expression of CHOP. Increased levels of Noxa also inactivated the remaining levels of Mcl-1 protein activity. Notably, these specific protein changes were essential to the apoptotic process because ABT-737 did not inhibit Mcl-1 protein activity and Mcl-1 overexpression blocked the apoptotic activity of ABT-737. Our results therefore suggest that this combination treatment could be developed as a potential therapy for human prostate cancer where overexpression of Pim kinases and antiapoptotic Bcl-2 family members drives tumor cell resistance to current anticancer therapies.
Citation Format: Jin H. Song, Andrew S. Kraft. Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737 [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C14.
Abstract C2: Nuclear factor I/C collaborates with androgen receptor in transcription regulation in prostate cancer
Authors: Yang Chong , Chng Kern Rei 
Published: May 2013

Abstract
Androgen receptor (AR) plays an important role in mediating the transcriptional regulatory network directing prostate cancer initiation, development and progression. In order to gain insights into the AR-dependent transcriptional regulatory network, we utilized Chromatin Immunoprecipitation-sequencing (ChIP-Seq) and generated genome-wide binding maps of AR in the LNCaP prostate cancer cell line. From our bioinformatic analyses of AR binding sites (ARBS), we found an enrichment of motifs belonging to the NFI family. We demonstrate that one member of the NFI family, NFIC, which has been shown to be over-expressed in clinical prostate tumors, overlaps with a large fraction of ARBS across the genome. Surprisingly, the recruitment of NFIC was independent of DHT treatment, indicating NFIC as a potential pioneer factor. Moreover, we showed NFIC was required for the global modulation of AR-dependent target genes including KLK2, KLK3, and TMPRSS2. Finally, we found that AR and NFIC co-associated genes are preferentially involved in cellular movement and apoptosis. Together, our results suggest NFIC is a novel collaborative factor in AR-mediated transcription.
Citation Format: Chong Yang, Kern Rei Chng. Nuclear factor I/C collaborates with androgen receptor in transcription regulation in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C2.
Abstract C21: LincRNA expression data analysis identifies prostate tumor subtypes with distinct biological processes
Authors: Mello-Grand Maurizia , Singh Vijay K. , Ghimenti Chiara , Scatolini Maria , Longoni Nicole , Curti Laura , Zitella Andrea , Gontero Paolo , Catapano Carlo V. , Carbone Giuseppina M. , Chiorino Giovanna 
Published: May 2013

Abstract
Prostate cancer (PCa) shows tremendous heterogeneity which makes it difficult to identify patients with an increased risk of disease recurrence. A better understanding of the biological mechanism of prostate cancer formation and progression is crucial for the discovery of new markers for this disease. In recent years it has become apparent that different non-coding RNAs are also implicated in prostate cancer. Several microRNAs are now associated with progression and classification of prostate cancer and other malignancies. The role played in progression and differentiation of distinct PCa subtypes by a recently discovered class of non-coding RNAs, called large intergenic non-coding RNAs (lincRNAs), has remained unexplored. LincRNAs are believed to have major consequences on gene expression patterns through epigenetic mechanisms. Thousands of lincRNAs have been identified in human tissues, but only few have been functionally characterized. To assess the role of lincRNAs in PCa, we analysed the expression pattern of nearly 28000 Entrez genes and 7500 unique lincRNAs in 56 primary PCas and 5 normal prostate tissues, using Agilent 8x60k arrays. Unsupervised clustering over 1610 lincRNAs, selected after filtering out non informative probes, classified 61 samples into 5 distinct classes. Anova analysis was done to identify genes specifically over or under expressed in each cluster and was followed by functional annotation analysis. Normal samples were separated into a cluster characterized by the down regulation of genes involved in chemotaxis and intracellular signaling cascade. The four tumor clusters showed up regulation of distinct biological processes, like cell cycle, chromatin organization and immune response, together with deregulation of MAP-kinase signaling through EGFR and members of the RAS family oncogene. These results show that sample classification based on lincRNA profiling is able to separate tumors into subgroups with distinct biological processes.
Citation Format: Maurizia Mello-Grand, Vijay K. Singh, Chiara Ghimenti, Maria Scatolini, Nicole Longoni, Laura Curti, Andrea Zitella, Paolo Gontero, Carlo V. Catapano, Giuseppina M. Carbone, Giovanna Chiorino. LincRNA expression data analysis identifies prostate tumor subtypes with distinct biological processes [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C21.
Abstract C25: The 16p13.3 genomic gain in prostate cancer: A role for PDK1 in disease progression
Authors: Choucair Khalil , Brimo Fadi , Cunha Isabela W , Aprikian Armen , Gleave Martin , Lapointe Jacques , Guérard Karl-Philippe , Ejdelman Joshua , Chevalier Simone , Yoshimoto Maisa , Scarlata Eleonora , Fazli Ladan , Sircar Kanishka , Squire Jeremy A. 
Published: May 2013

Abstract
Prostate cancer (PCa) is a leading cause of cancer death and distinguishing life threatening tumors from indolent ones is a major challenge. The identification and characterization of genomic alterations associated with advanced disease may lead to the development of new markers of progression and more efficient therapeutic approaches. Array-CGH data have shown that gain of chromosome 16p13.3 to be associated with lymph node (LN) metastases of PCa, but this region remained uncharacterized. Our goal was to establish the prognostic value of 16p13.3 gain, and identify the cancer relevant genes residing within this region. In this study, we performed Fluorescence In Situ Hybridization (FISH) to detect the copy number gain of chromosome 16p13.3 in 75 PCa samples including 10 lymph node (LN) metastases and their matched primary tumors, 9 transurethral resections of prostate (TURP) tissue samples of castration-resistant prostate cancer (CRPC), and 46 additional primary PCa specimens with clinicopathological parameters. We detected the gain in 5/10 LN metastases and 3/5 matched primary tumors, 3/9 CRPC samples, and 9/46 (20 %) primary tumors. In the latter set of samples, the 16p13.3 alteration was associated with high Gleason score (P=0.002) and elevated pre operative prostate specific antigen (PSA) levels (P=0.047). The levels of 16p13.3 gain were higher in LN metastasis and CRPC specimens compared to primary PCa (P&gt;0.05). Chromosome mapping revealed a focal gain that spans PDPK1 encoding the 3-Phosphoinositide-dependent protein kinase-1 (PDK1). RNA interference-mediated knock down of PDK1 in three different PCa cell lines reduced cell motility without affecting growth and re-expressing PDK1 rescued motility (P&gt;0.05). Our results support that the 16p13.3 gain is relevant to PCa progression and may represent an early marker of metastasis, since retrieved in primary PCa which is sampled by biopsies at time of diagnosis. PDK1 is implicated in PCa cell motility, a critical step for progression to metastasis. These findings provide further rationale for considering PDK1 as a target for cancer therapies and the development of new specific inhibitors of PDK1.
Citation Format: Khalil Choucair, Fadi Brimo, Isabela W Cunha, Armen Aprikian, Martin Gleave, Jacques Lapointe, Karl-Philippe Guérard, Joshua Ejdelman, Simone Chevalier, Maisa Yoshimoto, Eleonora Scarlata, Ladan Fazli, Kanishka Sircar, Jeremy A. Squire. The 16p13.3 genomic gain in prostate cancer: A role for PDK1 in disease progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C25.
Abstract C30: Use of targeted magnetic nanoparticles for imaging in prostate cancer
Authors: Russell Pamela J. , Soekmadji C , Thierry B , Cowin G , Strait-Gardner T , Verma N , Xiaochun Wang , Khatri A 
Published: May 2013

Abstract
Objective: Imaging techniques better than those conventionally used are needed to improve prostate cancer (PC) staging and read out of therapeutic effects in real time in treated patients. We aimed to perform preclinical evaluation of newly developed well-characterized, biocompatible, PC-targeted magnetic nanoparticles (MNPs) targeted to prostate cancer by conjugation with J591 (from N. Bander, Cornell, USA), an antibody which binds specifically to prostate specific membrane antigen (PSMA) which is expressed on the surface of ∼90% of PCs including castrate resistant prostate cancers; this binding results in internalization. The use of targeted MNPs should enhance the specificity and sensitivity of magnetic resonance imaging (MRI) to enable better staging of patients with PC and future targeted delivery of therapy.
Methods: MNPs were prepared, engineered to the appropriate size and conjugated with J591. There was no compromise in J591 cell binding or specificity for PSMA positive cells due to the conjugation, and Inductively Coupled Plasma Optical Emission Spectrometry and Prussian blue staining for iron indicated increased uptake of MNPs that were conjugated with the antibody. In vivo studies were performed in immunodepressed nude mice with subcutaneous LNCaP-LN3 (PSMA-positive) xenografts (post euthanasia using an 11.7T NMR system) or on live mice with orthotopic LNCaP xenografts, using a 16.4T MRI imaging system following intravenous injection of MNPs.
Results: Similar enhancement of MRI was obtained by NMR after injection of MNP or J591-MNP conjugates. Live imaging of mice given systemic J591-MNPs showed uptake into the prostate tumors.
Conclusions: The data indicate the promise of this technique in enabling imaging of small clusters of human prostate cancer cells. This should enable the effects of therapy to be determined by imaging in real time, improving patient management.
Citation Format: Pamela J. Russell, C Soekmadji, B Thierry, G Cowin, T Strait-Gardner, N Verma, Wang Xiaochun, A Khatri. Use of targeted magnetic nanoparticles for imaging in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C30.
Abstract C41: Nuclear Stat5a/b predicts early recurrence and prostate cancer-specific death in patients treated by radical prostatectomy.
Authors: Mirtti Tuomas , Leiby Benjamin E. , Stattin Pär , Bergh Anders , Nevalainen Marja T. , Abdulghani Junaid , Pavela Miia , Aaltonen Elina , Mamtani Anita , Alanen Kalle A. , Egevad Lars , Granfors Torvald , Josefsson Andreas 
Published: May 2013

Abstract
There is an urgent need for reliable markers to identify patients whose PCa is most likely to recur after initial therapy and progress to lethal disease. While Gleason score is considered the most accurate predictive marker for disease-specific mortality after primary treatment of localized prostate cancer (PCa), the majority of PCas cluster into intermediate group of Gleason scores 6 and 7 where there is considerable variation in treatment response, disease recurrence and disease-specific death. In this study, we analyzed the predictive value of elevated nuclear Stat5a/b expression in PCas treated by radical prostatectomy or active surveillance. The critical role of Stat5a/b in promotion of PCa growth and progression has been well-documented in preclinical PCa models. Specifically, Stat5a/b is critical for prostate cancer cell viability in vitro and for prostate tumor growth in vivo, and Stat5a/b promotes metastatic dissemination of prostate cancer in nude mice. Here, we demonstrate that in intermediate Gleason score PCas treated by radical prostatectomy, high levels of nuclear Stat5a/b predicted both early recurrence (univariate analysis; p&lt;0.0001, multivariate analysis; HR=0.55, p=0.017) and early PCa-specific death (univariate analysis; p=0.028). In addition, high nuclear Stat5a/b predicted early disease recurrence in both univariate (p&lt;0.0001) and multivariate (HR=0.62; p&lt;0.01) analysis in the entire cohort of patients treated by radical prostatectomy (n=562) regardless of the Gleason score. In the second group of patients treated by active surveillance, elevated nuclear Stat5a/b expression was associated with early PCa-specific death (p=0.0453) by univariate analysis (Cox regression analysis: 60% increased risk of death, p=0.034). If confirmed in future prospective studies, nuclear Stat5a/b may become a useful independent predictive marker of recurrence of lethal PCa after radical prostatectomy for intermediate Gleason score PCas.
Citation Format: Tuomas Mirtti, Benjamin E. Leiby, Pär Stattin, Anders Bergh, Marja T. Nevalainen, Junaid Abdulghani, Miia Pavela, Elina Aaltonen, Anita Mamtani, Kalle A. Alanen, Lars Egevad, Torvald Granfors, Andreas Josefsson. Nuclear Stat5a/b predicts early recurrence and prostate cancer-specific death in patients treated by radical prostatectomy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C41.
Abstract C43: Prognostic value of hypoxia-associated genes in prostate cancer
Authors: Gomez Christian R. , Vuk-Pavlovic Stanimir , Kosari Farhad , Munz Jan Marie , Schreiber Claire , Knutson Gaylord , Charlesworth Cristine , Karnes R. Jeffrey , Cheville John , Vasmatzis George 
Published: May 2013

Abstract
Tumor-associated hypoxia has been associated with malignant progression, metastasis and resistance to therapy. We studied the role of oxygen tension (pO2) in modulating the properties of cultured human prostate cancer (CaP) cells. In air, where oxygen tension (pO2) is approximately 20 kPa, cultured CaP cells expressed lower levels of transcripts associated with cancer and urologic disease; reducing pO2 to 2 kPa made these levels comparable to those in surgical CaP specimens suggesting that hypoxically cultured cells, rather than normoxically cultured cells, express genes at levels akin to those in tumor cells in situ. In human primary CaP tissue, transcripts of hypoxia-associated genes DLG7, CCNB1 and HMMR were overexpressed and associated with Gleason score and disease prognosis; this implies the potential prognostic value of these transcripts. While hypoxia affected the CaP cell proteome mostly quantitatively, it did affect expression of tumor–associated antigens and suggested the potential therapeutic relevance of the hypoxic antigenic landscape. Overall, our results suggest that hypoxia modifies cellular properties of cultured CaP cells towards a phenotype more similar to tumor cells in situ. Introduction of pO2 as a variable can constitute a tool for the identification of more effective prognostic biomarkers and development of better therapy for CaP and, possibly, other tumors.
Citation Format: Christian R. Gomez, Stanimir Vuk-Pavlovic, Farhad Kosari, Jan Marie Munz, Claire Schreiber, Gaylord Knutson, Cristine Charlesworth, R. Jeffrey Karnes, John Cheville, George Vasmatzis. Prognostic value of hypoxia-associated genes in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C43.
Abstract C5: Role of ID4 in the development of prostate in mouse
Authors: Sharma Pankaj , Nagappan Peri , Israel Mark A. , Chaudhary Jaideep 
Published: May 2013

Abstract
Introduction: The helix-loop-helix (HLH) family of transcriptional regulatory proteins are key players in a wide array of developmental processes. Studies in mice have convincingly demonstrated that HLH proteins are intimately involved in developmental events such as cellular differentiation and proliferation. The Id1, Id2, Id3 and Id4 gene products are closely related in their HLH regions and show similar affinities for the various E proteins but differ in their expression patterns. The function of Id proteins has recently been addressed by using a gene targeting approach in mice. Previous studies showed that Id1 null mutant mice do not exhibit abnormalities whereas reports from Id4−/− mice, found that Id4 is required for normal brain size, and regulates lateral expansion of the proliferative zone in the developing cortex and hippocampus. We have recently shown that Id4 is highly expressed in the normal human prostate, whereas its expression is epigenetically silenced in prostate cancer. However its role in normal prostate development and function is not known. Here, we demonstrate a role of Id4 in prostate development, by immunohistochemical techniques in Id4−/− mice.
Experimental procedures: To investigate the precise role of Id4 in cellular proliferation and development, normal H&E staining is performed on wild type and Id4−/− mouse prostate tissue. Expression of Id1, AR (Androgen receptor) and NKX3.1 on wild type and Id4−/− mouse prostate tissue was assessed by Immunohistochemistry.
Results: There was no change in expression of Id1 in wild type and Id4−/− mouse prostate. Androgen receptor and NKX3.1 expression in wild type mouse was mostly nuclear but there is no expression was observed in Id4−/− mouse prostate tissue. H&E staining of wild type and Id4−/− mouse prostate indicated a significant difference in the cellular morphology of Id4−/− mouse prostate tissue as compared to the wild type mouse prostate. In addition to cellular morphological changes, the size of androgen dependent reproductive tract organs such as seminal vesicle and prostate were significantly smaller in Id4−/− as compared to heterozygous and wild type mouse.
Conclusions: These results suggest a severe defect in androgen response pathway and support the role of Id4 in prostate development. Difference in the size of seminal vesicles and prostate in Id4−/− mouse shows the physiological role of Id4 in androgen target organs. Size difference could be due to lack of translocation of AR to nuclei however exact molecular mechanism remains to be investigated.
Acknowledgement: The research was supported by NIH/NCI-RO1CA128914 and in part by NIH/NCRR/RCMI G12RR03062.
Citation Format: Pankaj Sharma, Peri Nagappan, Mark A. Israel, Jaideep Chaudhary. Role of ID4 in the development of prostate in mouse [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C5.
Abstract C55: The basic helix loop helix transcription factor E2A is associated with prostate cancer
Authors: Patel Divya , Chaudhary Jaideep 
Published: May 2013

Abstract
Introduction: E2A (TCF3) is a multifunctional basic helix loop helix (bHLH), transcription factor. E2A regulates transcription of target genes by homo- or heterodimerization with other bHLH proteins such as MyoD, Mash, NeuroD and Id family of helix loop helix proteins. In general, E2A promotes cell differentiation, acts as a negative regulator of cell proliferation in normal cells and cancer cell lines and is required for normal B-cell development. Given the diverse biological pathways regulated/influenced by E2A little is known about its expression in cancer. Data mining approaches suggested that E2A is highly expressed in many cancers including prostate.
Experimental design: E2A protein expression was investigated in clinical prostate tumor samples on high density tissue microarray slides by Immunohistochemistry (IHC). The expression of E2A in PCA cell lines DU145 and PC3 was temporarily silenced using E2A siRNA (sc-35245, Santa Cruz Biotechnology) and its effect on the Proliferation, cell cycle, apoptosis, mitochondrial membrane potential and caspase 3/7 activation was determined. The underlying mechanism of action of E2A was investigated by analyzing the expression of potential E2A regulated genes involved in cell cycle.
Results: Consistent with increased E2A expression in prostate cancer suggested by meta-analysis, the E2A immunohistochemistry performed on prostate tissue microarrays demonstrated increased E2A expression in prostate cancer as compared to normal prostate. Silencing of E2A in prostate cancer cells DU145 and PC3 led to a significant reduction in proliferation due to G1 arrest that was in part mediated by increased CDKN1A(p21) and decreased Id1, Id3 and c-myc. E2A silencing in prostate cancer cell lines also resulted in increased apoptosis due to decrease in mitochondrial membrane permeability and increase in caspase 3/7 activity.
Conclusion: Based on our results, we propose that E2A could be an upstream regulator of Id1 and c-Myc which are highly expressed in prostate cancer. These results for the first time demonstrate that E2A could in fact acts as a tumor promoter at least in prostate cancer.
Acknowledgements: This study was supported by NIH/NCI RO1 CA128914 and NIH/NCRR/RCMI G12RR03062.
Citation Format: Divya Patel, Jaideep Chaudhary. The basic helix loop helix transcription factor E2A is associated with prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C55.