bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1998: Transcriptome analysis of hypoxic head and neck cancer cells uncovers intron retention in EIF2B5 as a mechanism to reduce protein synthesis
Authors: Brady Lauren K. , Wang Hejia , Radens Caleb , Radovich Milan , Maity Amit , Ivan Cristina , Ivan Mircea , Barash Yoseph , Koumenis Constantinos 
Published: July 2017

Abstract
Hypoxia is a key feature of solid tumors that contributes to resistance to therapy and reduced overall survival. Cellular adaptation to the hypoxic tumor microenvironment involves attenuation of energy-consuming processes such as macromolecular synthesis. We have identified RNA processing as another major process which is globally downregulated under hypoxic stress. By sequencing RNA of normoxic and hypoxic head and neck cancer cells, we observed widespread repression of genes that regulate RNA splicing and processing. As a result, we observed over 1,000 changes in relative mRNA isoform expression, including a significant increase in hypoxia-induced intron retention in nearly 100 genes. Genes observed to undergo intron retention in hypoxia included major regulators of RNA processing and protein synthesis, such as the translation initiation factor EIF2B5.
Surprisingly, hypoxia-induced intron retention in EIF2B5 creates a premature termination codon, which results in a truncated protein isoform of eIF2Bϵ. We provide evidence that this isoform acts in opposition to the full-length protein to inhibit translation under stringent hypoxic conditions. Moreover, this intron is expressed in solid cancers known to contain hypoxic fractions and is overexpressed in head and neck cancer in a stage-dependent manner compared to normal tissue.
To investigate how this intron is retained, we are examining the role of hypoxia-mediated changes in phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. Our data suggest that increased phosphorylation of the CTD may lead to transcriptional pausing and subsequent retention of intron 12 in EIF2B5. Furthermore, distinct sequence features at this locus, such as a weak splice site at the intron12:exon13 junction, may explain how this intron is selectively retained in hypoxic cells. These results implicate mRNA splicing as a key mechanism to induce alternate transcripts and subsequent protein isoforms under hypoxia that influence cellular adaptation to stress.
Citation Format: Lauren K. Brady, Hejia Wang, Caleb Radens, Milan Radovich, Amit Maity, Cristina Ivan, Mircea Ivan, Yoseph Barash, Constantinos Koumenis. Transcriptome analysis of hypoxic head and neck cancer cells uncovers intron retention in EIF2B5 as a mechanism to reduce protein synthesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1998. doi:10.1158/1538-7445.AM2017-1998
Abstract 2: Functional and mechanistic interrogation of BET bromodomain degraders for the treatment of metastatic castration resistant prostate cancer
Authors: Kregel Steven , Malik Rohit , Asangani Irfan A. , Wilder-Romans Kari , Jiang Xia , Apel Ingrid J. , Ravi Gautham , Tien Jean , Cao Xuhong , Feng Felix Y. , Speers Corey , Wang Shaomeng , Chinnaiyan Arul M. 
Published: July 2017

Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease with about 30,000 estimated annual deaths in U.S, with a vast majority of CRPC driven by androgen receptor (AR) signaling. AR-signaling is critical for the development and progression of prostate cancer, and AR also the main therapeutic clinical target. AR-targeted therapies, such as AR-antagonists, provide substantial benefits in the treatment of mCRPC; however, majority of patients fail these therapies and succumb to the disease. Therefore, there is a clear and pressing need to develop new therapeutics against the AR axis in CRPC. One such novel strategy for targeting the AR-pathway and inhibiting the growth of CRPC has been the use of bromodomain and extraterminal (BET) protein inhibitors such a JQ1. However, a new class of molecules that target BET bromodomain proteins through their proteasomal degradation can improve efficacy and specificity of these inhibitors. Based on our findings, we hypothesized that pharmacologic BET degradation represents an important advance in the treatment of CRPC, and may provide a novel therapeutic strategy for advanced prostate cancer. These inhibitors affect AR-positive prostate cancer cells preferentially over AR-negative and benign prostate epithelial cells, and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling, both in vivo and in vitro. The overall goal is to develop very potent small molecule that leads to the proteasomal-degradation of BET proteins, with optimized in vivo properties, and to provide a compelling scientific rationale, including detailed mechanistic insight, to facilitate advancement of BET degraders as a novel potential therapeutic strategy for patients with mCRPC.
Citation Format: Steven Kregel, Rohit Malik, Irfan A. Asangani, Kari Wilder-Romans, Xia Jiang, Ingrid J. Apel, Gautham Ravi, Jean Tien, Xuhong Cao, Felix Y. Feng, Corey Speers, Shaomeng Wang, Arul M. Chinnaiyan. Functional and mechanistic interrogation of BET bromodomain degraders for the treatment of metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2. doi:10.1158/1538-7445.AM2017-2
Abstract 2054: Cerivastatin overcomes the acquired resistance to crizotinib in EML4-ALK positive non-small cell lung cancer by controlling YAP activation
Authors: Yun Miran , Choi Hun Mi , Pyo Kyoung Ho , Cho Byoung Chul 
Published: July 2017

Abstract
Crizotinib is highly effective in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion. However, its efficacy has been limited by the development of acquired resistance, and the mechanisms of such resistance remain largely unknown. Herein, we investigated a possible candidate for circumventing the acquired resistance to crizotinib.
We established a model of acquired resistance to crizotinib (H3122-CR) by exposing EML4-ALK-positive H3122 lung cancer cells to increasing doses of crizotinib, and performed MTT screening using a library of FDA (Food and Drug Administration)-approved drugs composed of a collection of 640 clinically used compounds.
Our MTT screening identified that cerivastatin, a drug targeting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, significantly inhibited the cell growth in H3122-CR cells, which was completely restored by addition of geranylgeranyl pyrophosphate (GGPP), a key metabolite of mevalonate pathway. We also found that yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, was robustly accumulated in nucleus with a concomitant decrement of YAP phosphorylation in H3122-CR cells compared to parental cells. Importantly, inhibition of geranylgeranylation (GGylation) by GGTI-298 or cerivastatin markedly increased YAP phosphorylation, led to cytoplasmic translocation of YAP, and subsequently induced YAP inactivation. Moreover, the enrichment of EGFR signaling pathway and cell cycle signature including transcriptional targets of YAP was enhanced in H3122-CR cells, whose induction contributed YAP-mediated resistance to crizotinib. Inhibition of YAP function with siRNA or verteporfin as a YAP inhibitor greatly abrogated cell growth of H3122-CR cells by modulating cell cycle regulators and EGFR activation. Finally, we confirmed up-regulation of nuclear YAP expression in crizotinib-acquired resistant patient derived tumor xenograft (PDTX) models established from EML4-ALK positive NSCLC patients. Collectively, our findings define the GGylation-mediated YAP transcriptional activation as a new mechanism of resistance to crizotinib, providing a rationale for further exploring statins as a possible anticancer agent to overcome the acquired resistance to crizotinib in EML4-ALK positive NSCLC cells.
Citation Format: Miran Yun, Hun Mi Choi, Kyoung Ho Pyo, Byoung Chul Cho. Cerivastatin overcomes the acquired resistance to crizotinib in EML4-ALK positive non-small cell lung cancer by controlling YAP activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2054. doi:10.1158/1538-7445.AM2017-2054
Abstract 2107: Tetra-arsenic hexoxide induces G2/M cell cycle arrest, apoptosis, and autophagy via p38 MAPK- and AKT-mediated pathways in SW620 human colon cancer cells
Authors: Lee Won Sup , Yun Jeong Won , Kim Min Jeong , Nagappan Arulkumar , Lu Jing Nan , Chang Seong-Hwan , Jeong Jae-Hoon , Kim GonSup , Jung Jin-Myung , Hong Soon Chan 
Published: July 2017

Abstract
Tetraarsenic hexoxide (As4O6) has been used in Korean folk remedy for the treatment of cancer since the late 1980’s. Evidence suggests that As4O6 show anti-cancer effects, whose mechanisms are different from those for As2O3. However, the detailed anticancer mechanism is still unclear. Here, we investigated the anticancer effects of As4O6 on SW620 human colon cancer cells. As4O6 induced cell death in a dose-dependent manner. Flow cytometry analysis revealed that As4O6 increased the sub-G1 (apoptotic cell population) and G2/M phase population in a dose-dependent manner. Further, nuclear condensation and cleaved nuclei were also observed upon staining with Hoechst 33342 in As4O6-treated SW620 cells. Western blot revealed that As4O6 significantly down-regulated the cyclin B1, cdc 2, pro-caspases -3, -8 and -9, and up-regulated p21 and cleavage of PARP in SW620 cells. In addition, As4O6 increased the expression of death receptor 5 (DR5), suppressed Bcl-2 and XIAP family proteins, and promoted the conversion of LC3-I to LC3-II in a Beclin-1 independent manner. Interestingly, As4O6 dephosphorylated Akt and JNK and phosphorylated p38 MAPK, and the cell death was inhibited by p38 MAPK inhibitor; whereas Akt inhibitor augmented the As4O6 induced cell death, suggesting p38 MAPK and AKT were associated with As4O6-induced cell death. Taken together, these findings suggest that As4O6 induced G2/M arrest, apoptosis and autophagic cell death at least in part through p38 MAPK and AKT pathways in SW620 human colon cancer cells. This study may explain the anecdotal anticancer effects showing central necrosis with dormant status of cancers when treated by As4O6 as folk remedy.
Citation Format: Won Sup Lee, Jeong Won Yun, Min Jeong Kim, Arulkumar Nagappan, Jing Nan Lu, Seong-Hwan Chang, Jae-Hoon Jeong, GonSup Kim, Jin-Myung Jung, Soon Chan Hong. Tetra-arsenic hexoxide induces G2/M cell cycle arrest, apoptosis, and autophagy via p38 MAPK- and AKT-mediated pathways in SW620 human colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2107. doi:10.1158/1538-7445.AM2017-2107
Abstract 2116: Combining the power of different profiling approaches to better understand the activity of kinase inhibitor drugs
Authors: King Alastair J. , Parry Jesse J. , Burkart Samantha C. , Cavedine Lee R. , Cracchiolo Alyssa M. , Epkins Brogan A. , Garner Steven M. , Sindelar Timothy J. , Wageman Charles R. , Davies Stephen P. , Plater Andrew , Woodward Anna M. , Warrior Usha 
Published: July 2017

Abstract
Profiling of inhibitors for eventual therapeutic use is an essential part of drug discovery and development. Evaluating the in vitro potency of kinase inhibitors in a wide panel of enzyme assays is critical, not only to guiding SAR knowledge for improving drug design, but also for assessing selectivity, which has long-reaching consequences for both biological activity and safety. Evaluation of the same inhibitors in cellular models yields information on the activity of these inhibitors in a more physiologically relevant environment. However, while some selective kinase inhibitors show predictably selective profiles in cell proliferation assays, others do not. Thus, the biological context in which a kinase inhibitor functions, and the signaling networks influenced by inhibition of both the desired target and off-target activities, help to define how that inhibitor will work in a cellular setting and, ultimately, in a therapeutic application. We demonstrate the power of profiling several well-known kinase inhibitors in complementary panel assays, to predict behavior that has implications for clinical activity. The in vitro profiles of selective (trametinib, vemurafenib) and less selective (dasatinib, sorafenib) kinase inhibitors are shown and compared. With careful evaluation of their in vitro enzyme activity profiles in Eurofins’ KinaseProfiler™ panel, cellular response profiles in OncoPanel™, and predictive biomarker identification by univariate genomic analysis, a fuller picture of these inhibitors’ biological activity can be generated, and may be applied to predicting the therapeutic potential of such inhibitors. While, in some cases, clinical response is seen as expected, this kind of comprehensive analysis opens up the possibility for expanding clinical utility of an asset by potential repurposing for other indications. Collectively, this demonstrates not only the need to understand an inhibitor’s fundamental activity(ies) at its designated target(s), but also the importance of considering cellular context, when assessing its maximum potential clinical utility.
Citation Format: Alastair J. King, Jesse J. Parry, Samantha C. Burkart, Lee R. Cavedine, Alyssa M. Cracchiolo, Brogan A. Epkins, Steven M. Garner, Timothy J. Sindelar, Charles R. Wageman, Stephen P. Davies, Andrew Plater, Anna M. Woodward, Usha Warrior. Combining the power of different profiling approaches to better understand the activity of kinase inhibitor drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2116. doi:10.1158/1538-7445.AM2017-2116
Abstract 2141: Development of a novel miR-129 mimic with enhanced therapeutic potential for treatment of resistant colorectal cancer
Authors: Fesler Andrew T. , Wu Ning , Liu Hua , Ju Jingfang 
Published: July 2017

Abstract
Treatment of advanced stage colorectal cancer remains a clinical challenge associated with resistance to fluoropyrimidine based chemotherapy. There is an urgent need to discover and develop new strategies to enhance treatment efficacy in order to improve outcomes for these patients. Non-coding microRNAs (miRNAs) have important functions as oncogenes or tumor suppressor genes in the regulation of cancer development and progression. Recently, miRNAs have emerged as potential therapeutic options. We have previously identified miR-129 as a tumor suppressor miRNA and potential therapeutic candidate in colorectal cancer. The expression of miR-129 is progressively lost in colorectal cancer patients and is an important regulator of apoptosis through the targeting of genes such as BCL-2. miR-129 was also found to enhance 5-flurouracil (5-FU) cytotoxicity in vitro and in vivo. To further developing miR-129 based novel therapeutics in colorectal cancer, we have designed a modified version of miR-129 to enhance stability and efficacy. The miR-129 mimic is significantly more potent in inhibiting proliferation of a panel of colon cancer cell lines than the native miR-129 precursor, with 79% reduction by miR-129 mimic compared to 38% for native precursor. The miR-129 mimic induces profound cell cycle arrest at the G1/S checkpoint. The G1/S ratio increased 3.8 fold compared to control when cells were transfected with miR-129 mimic. We also demonstrated that the miR-129 mimic retains its target specificity to BCL-2, TS and E2F3. The therapeutic potential of miR-129 mimic was demonstrated in vivo mouse colon tumor models as a potent inhibitor of tumor growth and metastasis. As a result, miR-129 mimic has a great potential to be further developed as a novel therapeutic drug for treatment of advanced colorectal cancer.
Citation Format: Andrew T. Fesler, Ning Wu, Hua Liu, Jingfang Ju. Development of a novel miR-129 mimic with enhanced therapeutic potential for treatment of resistant colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2141. doi:10.1158/1538-7445.AM2017-2141
Abstract 2149: Unusual expression of HPRT on the surface of the colorectal cancer cell lines HT29 and SW620
Authors: Weagel Evita G. , Townsend Michelle H. , Anderson Michael D. , Velazquez Edwin J. , Weber K Scott , Robison Richard A. , O'Neill Kim L. 
Published: July 2017

Abstract
Colorectal cancer is one of the most common cancers in the world, affecting nearly 1.2 million people in the United States alone. The aim of this study is to investigate the salvage pathway enzyme HPRT as a possible biomarker in two colorectal cancer cell lines: HT29 and SW620. HPRT is a transferase in the purine salvage pathway that functions primarily by catalyzing the conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. Because of its role in proliferation and cell cycle regulation, we hypothesized an increase in HPRT expression within cancer cells, which could potentially lead to presentation on the surface of the cell. HPRT surface localization was assessed utilizing confocal microscopy, flow cytometry, and scanning electron microscopy. These techniques allowed us to visualize HPRT on the plasma membrane and quantify expression. There was statistically significant expression of HPRT on the surface of both HT29 and SW620 cells with a 28% and 58% fluorescent shift in the population, respectively. Confocal microscopy images revealed overlap between cells stained with a membrane dye and anti-HPRT FITC antibody, which indicates a direct relationship between HPRT and the plasma membrane of SW620 cells. To visualize the location of HPRT on the plasma membrane, anti-HPRT antibodies were labelled with gold and protein presence was quantified using an electron microscope, which measured the gold elemental weight percentage of each sample. When exposed to anti-HPRT antibody, the gold weight percentage of the samples significantly increased with 12.4% gold in SW620 cells and 11.2% gold in HT29 cells, indicating significant HPRT surface presence. The observed localization of HPRT to the plasma membrane was variable between the two different cancer cell lines. SW620 cells, which are faster growing and more aggressive, had significantly higher HPRT presentation that HT29 cells. These data collectively suggest that HPRT may be a possible biomarker target for the identification and possible treatment of colorectal cancer cells.
Citation Format: Evita G. Weagel, Michelle H. Townsend, Michael D. Anderson, Edwin J. Velazquez, K Scott Weber, Richard A. Robison, Kim L. O'Neill. Unusual expression of HPRT on the surface of the colorectal cancer cell lines HT29 and SW620 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2149. doi:10.1158/1538-7445.AM2017-2149
Abstract 2155: Small molecule NSC59984 suppresses cancer cell growth under hypoxia
Authors: Zhang Shengliang , Zhou Lanlan , El-Deiry Wafik S. 
Published: July 2017

Abstract
Hypoxia is one of the main features of solid tumors, contributes to drug resistance and is associated with poor prognosis. We have reported that a small-molecule NSC59984 restores p53 signaling and degrades mutant p53 protein in cancer cells. We find that NSC59984-mediated p53 signaling restoration and mutant p53 degradation is significantly blocked by NAC, an inhibitor of reactive oxygen species (ROS), while, further enhanced by BSO, a chemical compound increasing ROS in cells. These results suggest that ROS is a factor required for the effect of NSC59984 on cancer cells. Cellular ROS is produced by hypoxia in solid tumors. We investigated the effect of NSC59984 on p53 pathway and cell death in p53 mutant colorectal cancer (CRC) cells cultured under hypoxia. NSC59984 increases p53 signaling in p53 mutant cancer cells under hypoxia, as it does under normoxia. The effect of NSC59984 under hypoxia is blocked by NAC. Moreover, NSC59984 decreases cancer cell viability in a dose-dependent manner under hypoxia similar to normoxia. Our results suggest that NSC59984 inhibits cancer cell growth under hypoxia. Hypoxia has been known to increase cancer stem cells in tumors, which is one of the reasons causing drug resistance. We then evaluate the effect of NSC59984 on the stem cell growth. NSC59984 significantly reduces colonosphere formation of SW480, DLD-1 and HT29 cells. CRC stem cell markers such as CD44 and ALDH are decreased in colonospheres upon NSC59984 treatment, suggesting that NSC59984 inhibits stem cell self-renewal or/and growth. Our results provide the rationale for administration of NSC59984 in solid tumors with or without hypoxia and in combination treatment with ROS activators.
Citation Format: Shengliang Zhang, Lanlan Zhou, Wafik S. El-Deiry. Small molecule NSC59984 suppresses cancer cell growth under hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2155. doi:10.1158/1538-7445.AM2017-2155
Abstract 2179: Targeted delivery of nanoparticulate cytochrome c into GL261 glioma cells through the proton-coupled folate transporter
Authors: Kucheryavykh Yuriy , Ortiz-Rivera Jescelica , Inyushin Michael , Cubano Luis , Morales-Cruz Moraima , Cruz-Montañez Alejandra , Griebenow Kai , Kucheryavykh Lilia 
Published: July 2017

Abstract
In this study we identified the proton-coupled folate transporter (PCFT) as a route for targeted delivery of drugs to glioma cells. Using the techniques of confocal imaging, western blotting, and siRNA knockdown against the PCFT (encoded by the SLC46A1 gene), we demonstrated that Gl261 glioma cells, but not primary cultured astrocytes, express the PCFT, which provides selective internalization of folic acid (FA)-conjugated cytochrome c-containing nanoparticles (FA-Cyt c NPs), followed by glioma cell death. FA-Cyt c NPs, used at a concentration of 100 µg/ml, had no cytotoxic effects in astrocytes but caused 40% death in GL261 cells. Whole-cell patch clamp recording revealed FA-induced membrane currents, with maximum activity at pH 6.0, which is specific for the PCFT. Currents were reduced by siRNA PCFT knockdown in a similar manner as by application of FA-Cyt c NPs, indicating that the PCFT is a major carrier of FA and a route for internalization of FA-conjugated NPs in GL261 cells. We conclude that the PCFT provides a mechanism for targeted delivery of FA-conjugated nanodrugs to glioma cells with high specificity for GL261 cells, effectively causing apoptosis in these cells, and provides a starting point for the development of efficient methods for treating gliomas. The research was supported by NIH grants SC2GM102040, SC2GM095410, G12MD007583, R25GM110513, and US Department of Education Grant P031S130068.
Citation Format: Yuriy Kucheryavykh, Jescelica Ortiz-Rivera, Michael Inyushin, Luis Cubano, Moraima Morales-Cruz, Alejandra Cruz-Montañez, Kai Griebenow, Lilia Kucheryavykh. Targeted delivery of nanoparticulate cytochrome c into GL261 glioma cells through the proton-coupled folate transporter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2179. doi:10.1158/1538-7445.AM2017-2179