bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A042: Modulation of translation regulation by N6-methyladenosine in prostate cancer
Authors: Cotter Kellie A. , Meyer Kate D. , Benelli Matteo , Cohen Sandra , Jaffrey Samie , Demichelis Francesca , Rubin Mark 
Published: February 2019

Abstract
Recent evidence has highlighted the role of N6-methyladenosine (m6A) in post-transcriptional control of mRNA, in particular in altering translation efficiency. The demethylase (ALKBH5) and a methyltransferase (METTL3), which control m6A placement, are down- and upregulated, respectively, in prostate adenocarcinoma (PCa). This leads to the hypothesis that PCa exhibits alterations in m6A, and by extension changes in the translation efficiency of those transcripts. In this study we seek to produce an epitranscriptome map of m6A in PCa using single-nucleotide m6A mapping (miCLIP) of benign (RWPE) and PCa (LNCaP) cell lines. Distribution of m6A marks within transcripts mimics those seen in previous datasets: most peaks map to regions in cds or 3′ UTR, and show enrichment surrounding the TSS and stop codon. Overall miCLIP identifies over 10,000 transcripts with at least one m6A in the two cell lines, with many androgen-signaling genes and oncogenes exhibiting a high number of m6A sites. In order to assess the role of m6A in alterations in translation efficiency, we combined ribosome footprint profiling with RNA-seq in cells with and without METTL3 knockdown. This analysis identified several oncogenes as targets for translational regulation by m6A along with multiple genes related to cell migration, metastasis, and integrin signaling. These results validate m6A as a potentially important additional mechanism of gene regulation at the level of translation in PCa. Further, by allowing for the identification of changes in expression at the protein level previously undetectable by gene expression analysis alone, these findings may lead to the discovery of novel biomarkers or pathways as potential targets for treatment.
Citation Format: Kellie A. Cotter, Kate D. Meyer, Matteo Benelli, Sandra Cohen, Samie Jaffrey, Francesca Demichelis, Mark Rubin. Modulation of translation regulation by N6-methyladenosine in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A042.
Abstract A043: Bypass kinase pathways lead to acquired CDK4/6 inhibitor resistance in prostate cancer
Authors: Leeuw Renee de , McNair Christopher M. , Schiewer Matthew J. , Neupane Neermala P. , Augello Michael A. , Li Zhen , Cheng Larry , Yoshida Akihiro , Diehl J. Alan , Hazard E Starr , McCourtney Sean M. , Hardiman Gary , Hussain Maha H. , Drake Justin M. , Kelly Wm. Kevin , Knudsen Karen E. 
Published: February 2019

Abstract
Cyclin dependent kinase-4/6 (CDK4/6) kinase inhibitors have shown clinical benefit in treatment of solid tumor types, including breast cancer. However, resistance is common, and the underpinning mechanisms of action are not well understood. Given the dependence of CDK4/6 inhibitors on retinoblastoma tumor suppressor (RB) function for activity, this class of agents may be particularly effective in tumor types for which RB loss is infrequent or occurs late in tumor progression. Here, models of acquired palbociclib resistance were generated in early-stage, RB-positive cancers, wherein it was shown that acquired palbociclib resistance resulted in cross-resistance to other CDK4/6 inhibitors under clinical testing. Furthermore, cells showing acquired resistance exhibited aggressive in vitro and in vivo phenotypes without genetic loss of RB or RB pathway members, including enhanced proliferative capacity, migratory potential, and characteristics of epithelial-to-mesenchymal transition. Further analyses through integration of RNA sequencing and phospho-proteomics identified activation of the MAPK signaling pathway as a mediator of CDK4/6 inhibitor resistance, capable of bypassing CDK4/6 activity. However, this altered kinase dependence resulted in sensitization to MEK inhibitors, suggestive of new clinical opportunities in CDK4/6-resistant tumors. In sum, the studies herein not only identify activation of the MAPK pathway as capable of bypassing the CDK4/6 requirement and promoting aggressive tumor characteristics, but also nominate MEK inhibitors as potential mechanisms to treat or prevent CDK4/6 inhibitor resistance.
Citation Format: Renee de Leeuw, Christopher M. McNair, Matthew J. Schiewer, Neermala P. Neupane, Michael A. Augello, Zhen Li, Larry Cheng, Akihiro Yoshida, J. Alan Diehl, E Starr Hazard, Sean M. McCourtney, Gary Hardiman, Maha H. Hussain, Justin M. Drake, Wm. Kevin Kelly, Karen E. Knudsen. Bypass kinase pathways lead to acquired CDK4/6 inhibitor resistance in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A043.
Abstract A056: Is non-mutated GPR89A protein a potential drug target in prostate cancer?
Authors: Ma Yuanjun , Liu Yanling , Nilsson Sten , Li Chunde 
Published: February 2019

Abstract
Mutated genes as drug targets to treat cancer are a widely known concept; however, the effect is moderate. Targeting nonmutated genes is an alternative and probably has potential to benefit patients. GPR89A, as a nonmutated protein in prostate cancer, was evaluated as a drug target in this project. Data showed that GPR89A knockdown could induce high cancer cell death rate. Combination use of GPR89A siRNA and docetaxel triggered synergism effect, which implicates a possibility that GPR89A inhibitors could be used together with docetaxel. The high-throughput screening discovered 39 drug candidates that could reduce cancer cell viability and GPR89A expression simultaneously. These findings highlight the importance of nonmutated genes in cancer progression. Targeting nonmutated genes, e.g., GPR89A, should be evaluated further to find significant association between these genes/proteins and cancers.
Citation Format: Yuanjun Ma, Yanling Liu, Sten Nilsson, Chunde Li. Is non-mutated GPR89A protein a potential drug target in prostate cancer? [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A056.
Abstract A070: Targeting N-myristoyltransferase 1 inhibits prostate cancer progression
Authors: Alsaidan Omar , Kim Sungjin , Goodwin Octavia , Li Qianjin , Bai Aiping , Bielawska Alicja , Zheng George , Lebedyeva Iryna , Albers Thomas , Norris James S. , Pegan Scott D. , Cai Houjian 
Published: February 2019

Abstract
N-myristoyltransferase (NMT) facilitates co/post-translational myristoylation of several oncogenic proteins, regulating their functions in tumor progression. N-myristoyltransferase (NMT), which has been shown to be upregulated in a variety of cancers, is overexpressed in androgen-independent prostate cancer cells. We demonstrate that genetically, ablation of NMT1 inhibited proliferation of prostate cancer cells, tumor growth, and suppressed myristoylation profile of prostate cancer cells. Screening a panel of myristoyl-CoA analogs against purified human NMT1 protein leads to identifying the B13 as an inhibitor for NMT1. B13 significantly suppressed prostate cancer cell proliferation, migration, and invasion by cell cycle arrest, and inhibited the growth of prostate xenograft tumors with minimal pathologic effect on major organs in vivo. Structure activity relationship based optimization of B13 led to LCL204, which showed better inhibitory properties towards NMT1. We demonstrate that targeting protein myristoylation is a potential therapeutic approach to inhibit prostate tumor progression.
Citation Format: Omar Alsaidan, Sungjin Kim, Octavia Goodwin, Qianjin Li, Aiping Bai, Alicja Bielawska, George Zheng, Iryna Lebedyeva, Thomas Albers, James S. Norris, Scott D. Pegan, Houjian Cai. Targeting N-myristoyltransferase 1 inhibits prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A070.
Abstract A074: Aberrant activation of a gastrointestinal transcriptional circuit in prostate cancer mediates castration resistance
Authors: Shukla Shipra , Cyrta Joanna , Murphy Devan , Walczak Edward , Ran Leili , Agrawal Praveen , Xie Yuanyuan , Chen Yuedan , Wang Shangqian , Zhan Yu , Wong Wai Pung E. , Sboner Andrea , Beltran Himisha , Mosquera Juan-Miguel , Sher Jessica , Cao Zhen , Wongvipat John , Koche Richard P. , Gopalan Anuradha , Zheng Deyou , Rubin Mark , Scher Howard I. , Chi Ping , Chen Yu 
Published: February 2019

Abstract
Prostate cancer exhibits a remarkable lineage-specific dependence on androgen signaling. Lineage-directed therapy using androgen deprivation has been the mainstay of prostate cancer treatment for 70 years. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. Our studies found that an aberrant gastrointestinal lineage transcriptome is expressed in ~5% of primary prostate cancer that is characterized by abbreviated response to androgen deprivation therapy and in ~30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal lineage genes, independent of AR signaling. In HNF4G/1A-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the GI transcriptome, chromatin landscape and leads to relative castration resistance.
Citation Format: Shipra Shukla, Joanna Cyrta, Devan Murphy, Edward Walczak, Leili Ran, Praveen Agrawal, Yuanyuan Xie, Yuedan Chen, Shangqian Wang, Yu Zhan, Wai Pung E. Wong, Andrea Sboner, Himisha Beltran, Juan-Miguel Mosquera, Jessica Sher, Zhen Cao, John Wongvipat, Richard P. Koche, Anuradha Gopalan, Deyou Zheng, Mark Rubin, Howard I. Scher, Ping Chi, Yu Chen. Aberrant activation of a gastrointestinal transcriptional circuit in prostate cancer mediates castration resistance [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A074.
Abstract B009: Amalgamated c-MYC activation and p53 loss drives rapid prostate tumorigenesis and lethal epididymis tumors in Ai-Myc model
Authors: Wang Wei , Meng Yanling , Dong Bingning , Yang Feng 
Published: February 2019

Abstract
c-Myc is one of the most frequently amplified genes in human cancers, including prostate cancer (PCa). It is also frequently overexpressed in PCa as early as prostatic intraepithelial neoplasia (PIN). c-Myc overexpression has been shown to induce pathologic changes of mouse prostate, from mostly normal histology, hyperplasia, mPIN, to invasive prostate tumors. Here we describe an Ai-Myc model designed to ectopically express c-Myc and an enhanced luciferase (Luc2) in any tissue in a Cre-inducible manner. To study PCa, Ai-Myc mice were crossed with PB-Cre4 mice to turn on c-Myc expression in prostate epithelia. Once turned on, the expression of transgenes no longer depends on androgen, which allows studying castration of PCa. These mice developed early onset of mPIN along with enhanced apoptosis; only a small fraction of aged mice developed prostate tumors, indicating that c-Myc alone is not sufficient for effectively driving prostate tumorigenesis. Although mutation or loss of p53 is not common in early PCa, it is strongly correlated to PCa disease stages, metastasis, and castration resistance, and p53 is the most significantly altered gene in metastatic castration-resistant PCa. Therefore, we performed conditional ablation of p53 in the PB-Cre4/Ai-Myc mice to model a significant fraction of advanced PCa and to investigate whether loss of p53 inhibits c-Myc oncogene induced apoptosis for robust prostate tumorigenesis. Indeed, these mice rapidly developed prostate tumors; however, within 3-5 months, all mice also unexpectedly developed lethal epididymis tumors, a rare type of cancer in human. Early castration to fully remove epididymis followed by implantation of testosterone pellets allows these mice to develop advanced prostate tumors with metastasis. In summary, we have developed a novel c-Myc induced PCa model and demonstrated that amalgamated c-Myc activation and p53 loss drives rapid prostate tumorigenesis. Our study also unexpectedly revealed a potent tumorigenesis pathway for cancer of epididymis, a rare and poorly understood type of cancer accounting for at most 0.03% of male cancers.
Citation Format: Wei Wang, Yanling Meng, Bingning Dong, Feng Yang. Amalgamated c-MYC activation and p53 loss drives rapid prostate tumorigenesis and lethal epididymis tumors in Ai-Myc model [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B009.
Abstract B023: Identification and biochemical validation of piperlongumine as a potent therapeutic against neuroendocrine prostate cancer
Authors: Yadav Kamlesh K. , Shameer Khader , Stockert Jennifer A. , Elaiho Cordelia , Readhead Ben , Yadav Shalini S. , Dudley Joel , Tewari Ashutosh K. 
Published: February 2019

Abstract
Introduction and Objectives: Recent studies have highlighted the existence of a highly lethal and drug-resistant variant of prostate cancer (PCa) termed neuroendocrine prostate cancer (NEPC). We have used a genomics-based drug-repositioning approach to identify piperlongumine, a natural product constituent of the fruit of the long pepper (Piper longum), as a potential therapeutic against NEPC. The efficacy of this drug was tested in the NEPC cell line model NCI-H660 and compared to several other PCa cell lines in a modified WST-1 assay. Preclinical testing in mouse xenograft models of NEPC was also undertaken. Finally, the ability of piperlongumine to inhibit p-STAT3 signaling and promote apoptosis in cell lines and extracted tumors were measured by Western blot analyses.
Methods: PCa cell lines (LNCaP, 22Rv1, Du145, PC3, H660, and RWPE) were grown in complete media (RPM1 10% FBS, Advanced DMEM 5% FBS, or Keratinocyte-SFM) and treated with piperlongumine for 3 or 7 days. IC50 values were generated from WST assay data using Prism6. Nude mice (n=5) were injected with 1.5x106 H660 cells on each flank, and intraperitoneally administered with either 2.5mg/kg piperlongumine (n=3) or DMSO (n=2) daily for 3 weeks after tumors formed 200mm3 in volume. Tumor volume was measured daily with calipers. Western blot analyses were performed on protein lysates extracted from tumors and PCa cells treated with 0-10 μM of drug.
Results: Piperlongumine was highly effective in inhibiting the growth of H660 cells
(IC50 = 0.4 μM) compared to LNCaP, 22Rv1, Du145, PC3, and RWPE cells. On average, the growth rate of untreated tumors was 2.7 times greater than those treated was piperlongumine. Treated H660 cells exhibited significant inhibition of p-STAT3 and increases in cPARP1 levels while other cell lines displayed little to no fluctuation.
Conclusions: Using drug-repositioning approaches we have identified a lead compound that inhibits the growth of the highly drug-resistant NEPC cell line NCI-H660. Remarkably, piperlongumine happens to be a water-soluble plant product with no known side effects.
Citation Format: Kamlesh K. Yadav, Khader Shameer, Jennifer A. Stockert, Cordelia Elaiho, Ben Readhead, Shalini S. Yadav, Joel Dudley, Ashutosh K. Tewari. Identification and biochemical validation of piperlongumine as a potent therapeutic against neuroendocrine prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B023.
Abstract B030: MEK5 downregulation enhances radiosensitization of human prostate cancer cells by inhibiting DNA repair
Authors: Broustas Constantinos G. 
Published: February 2019

Abstract
Radiotherapy is commonly used to treat a variety of solid human tumors, including localized prostate cancer. However, treatment failure almost always ensues due to tumor intrinsic or acquired radioresistance.
Mitogen-activated protein kinase kinase 5 (MAP2K5 or MEK5), belongs to the family of MAP kinases. It is activated by the upstream kinases MEKK2 and MEKK3 at Ser311/Thr315. MEK5, in turn, phosphorylates and activates extracellular signal-regulated kinase 5 (ERK5 or BMK1) at Thr218/Tyr220. MEK5/ERK5 pathway plays a pivotal role in tumor initiation and progression. MEK5 protein is overexpressed in prostate cancer cells compared with normal prostate epithelial cells, and MEK5 levels are correlated with prostate cancer metastasis. High expression of ERK5 in prostate cancer is also found to correlate with poor disease-specific survival and can serve as an independent prognostic factor.
To determine whether the MEK5/ERK5 pathway is activated in response to ionizing radiation (IR), RNA interference was used to deplete MEK5 from PC3 and DU145 cells. Western blot analysis demonstrated that control cells with normal levels of MEK5 exposed to 3-Gy γ-rays had an increase in phospho-ERK5 levels at 5 and 15 min post-IR, diminishing at later time points. No activated ERK5 was detected in MEK5-depleted cells. Downregulation of MEK5 did not impact on cell cycle checkpoint activation in irradiated cells. In contrast, depletion of MEK5 markedly impaired phosphorylation of DNA-PKcs at Ser2056 in response to IR treatment. Furthermore, MEK5 knockdown did not influence the initial appearance of γH2AX or 53BP1 foci after irradiation, but significantly delayed the resolution of radiation-induced γH2AX and 53BP1 foci, detectable even 48 h post-irradiation, indicating a DNA repair defect. Cell based assay showed that nonhomologous end-joining is compromised in PC3 cells with ablated MEK5 protein expression. Finally, long-term clonogenic survival analyses and short-term cell growth assays indicated that MEK5 knockdown sensitized PC3 and DU145 prostate cancer cell lines to IR. Likewise, the topoisomerase II inhibitor etoposide that causes double-strand breaks also sensitized MEK5-depleted cells.
These data indicate that MEK5 influences the response of prostate cancer cells to radiation and MEK5 downregulation is associated with delayed double-strand break repair kinetics. Inhibition of MEK5 in combination with radiation may provide a strategy to improve survival of prostate cancer patients.
Citation Format: Constantinos G. Broustas. MEK5 downregulation enhances radiosensitization of human prostate cancer cells by inhibiting DNA repair [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B030.
Abstract B047: Biochemical parameters of prostate cancer patients in Nigeria
Authors: Iweala Emeka , Rotimi Solomon , Kanu Faith , Ogo Chidiebere 
Published: February 2019

Abstract
The screening of biochemical parameters of cancer patients and their development into reliable and specific diagnostic and prognostic biomarkers has been reported in several studies. The biochemical signature of prostate cancer patients in Nigeria may vary from others and can serve as important leads in discovery of new biomarkers for the disease. This will ultimately provide more information on the specific causes and prognosis of the disease as well as improve its diagnosis and management. This study examined some biochemical parameters including alanine transaminase (ALT), alkaline phosphatase (ALP), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TRIG), reduced glutathione (GSH), lipid peroxidation and peroxidase (POD) in the plasma of prostate cancer patients and controls. The data obtained indicate that there were no significant differences in the ALT, LDL, HDL, and POD while ALP and TRIG were significantly increased. Also, there was a significant reduction in GSH. This indicates the possible implication of ALP, TRIG, and GSH in prostate cancer disease in Nigeria and their potential to be further developed into diagnostic and prognostic biomarkers.
Citation Format: Emeka Iweala, Solomon Rotimi, Faith Kanu, Chidiebere Ogo. Biochemical parameters of prostate cancer patients in Nigeria [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B047.
Abstract B048: Androgen metabolism and incidence of prostate cancer in Nigeria
Authors: Rotimi Solomon , Ogo Chidiebere , Ogunlana Olubanke , Chinedu Shalom , Iweala Emeka 
Published: February 2019

Abstract
The risk of prostate cancer among blacks, especially of Nigerian descent, is higher than other races. This could be attributed to biologic and genetic variability. The role of androgen metabolism in prognosis of prostate cancer has been delineated and reported. One of the enzymes involved in androgen metabolism is CYP3A4, which has not been studied in Nigerian men afflicted with prostate cancer. Racial differences in this functional gene may contribute to variations in incidence of prostate cancer across ethnic divides. Therefore, identifying a diagnostic and prognostic biomarker such as CYP3A4 polymorphism for prostate cancer in black men will improve the treatment and management of the disease. In this study, we investigated the genotypes of CYP3A4 of prostate cancer patients from Nigeria for possible correlation to the high incidence of the disease in Nigerian men. The results obtained showed a preponderance of the GG genotypes, which indicates a possible correlation between this genotype of CYP3A4 and higher risk of prostate cancer among Nigerian men.
Citation Format: Solomon Rotimi, Chidiebere Ogo, Olubanke Ogunlana, Shalom Chinedu, Emeka Iweala. Androgen metabolism and incidence of prostate cancer in Nigeria [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B048.