bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5424: Improved anticancer activity of clotam as a copper-complex
Authors: Sankpal Umesh T. , Patel Rafid , Arechiga Bianca , Hunter Abigail , Chhabra Jaya , Brown Deondra T. , Gurung Raj K. , Holder Alvin A. , Basha Riyaz M. 
Published: August 2018

Abstract
Clotam (tolfenamic acid or TA) is a nonsteroidal anti-inflammatory drug used to treat migraine headaches. Research from our laboratory and other groups has demonstrated that TA also acts as an anticancer agent in several adult and pediatric cancer models. It is well established that the anticancer activity of TA is partly mediated by its ability to downregulate the specificity protein (Sp) family of transcription factors and their downstream targets, notably the inhibitor of apoptosis protein family member survivin. Both Sp1 and survivin are upregulated in cancer cells and are associated with poor prognosis, making them ideal therapeutic targets. It was recently suggested that the therapeutic potential of TA could be enhanced by forming a complex with copper(II). In this study we synthesized a copper(II) complex of TA (Cu-TA) and tested its anticancer activity using cell lines representing various cancers such as breast, prostate, pancreatic, brain, colon, neuroblastoma, medulloblastoma, and sarcoma. The compound was synthesized and its purity was assessed by UV-visible spectrophotometry. Purified compound (&gt;98%) was dissolved in DMSO and its antiproliferative activity was determined using the CellTiter-Glo cell viability assay kit. In our initial screening various cancer cells were treated with increasing concentration of Cu-TA or TA, and cell viability was assessed at 24 and 48h post-treatment. The effect of Cu-TA on expression of Sp1 and survivin was determined by Western blot analysis of lysates prepared using cells treated with Cu-TA or TA for 48h. We also studied the effect of Cu-TA on cell cycle and apoptosis using medulloblastoma cell lines. Both Cu-TA and TA decreased cell viability in a dose-dependent manner; however, Cu-TA consistently had lower IC50 values in all the cell lines tested, suggesting its higher efficacy compared to TA. In line with the viability results, Western blot analysis of survivin expression demonstrated that Cu-TA was more effective in inhibiting its expression compared to TA. Also, treatment of medulloblastoma cells with Cu-TA resulted in cell cycle arrest in G0/G1 phase accompanied by an increased apoptosis as determined by annexin-V staining. This preliminary screening demonstrates the potential of Cu-TA as an effective anticancer agent with the ability to target survivin. Further studies to delineate the mechanism of action of Cu-TA are under way.
Citation Format: Umesh T. Sankpal, Rafid Patel, Bianca Arechiga, Abigail Hunter, Jaya Chhabra, Deondra T. Brown, Raj K. Gurung, Alvin A. Holder, Riyaz M. Basha. Improved anticancer activity of clotam as a copper-complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5424.
Abstract 5425: Investigating the effects of p53 activation and HDAC inhibition on genes associated with poor prognosis prostate cancer
Authors: Gregg Gemma M. , Falcone Fiammetta , Lees Andrea , Quinn Gerard , Gallagher Peter , Kennedy Richard , Mills Ian I. , McDade Simon S. 
Published: August 2018

Abstract
Background
Prostate cancer (PCa) is now the most commonly diagnosed malignancy in men worldwide. SOC combines radiotherapy with ADT, however recurrence rate remains unacceptably high and many men present with late stage aggressive and metastatic disease, with poor prognosis and limited treatment options.
Despite tumor suppressor p53 being mutated in approximately 50% of human tumors, it has been reported that p53 alteration occurs in only 12% of primary prostate tumors. Emerging data links epigenetic-mediated gene silencing as a major differentiator between aggressive and indolent disease that is associated with up-regulation of key cell cycle regulator FOXM1, which is known to be suppressed by p53. HDAC inhibitors (HDACi) are an emerging class of epigenetic modifying anti-cancer agents, which we hypothesises will enhance p53 activity, cell death and alter patterns of gene expression to targeting p53 dependent and independent vulnerabilities in PCa.
Methods
We used basally p53 deficient/proficient PCa models (PC3/LNCaP) and novel C4-2B and LNCap p53 CRISPR-Cas9 knockout models to investigate the combination effects of Nutlin 3A or radiation (IR) with class 1 HDACi Entinostat by Annexin V/PI Flow Cytometry and Western Blot. Transcriptional effects were evaluated by RT-PCR and RNA-seq analysis. TCGA mutational and RNA-seq data were used to link p53 mutation with altered gene expression and outcome.
Results
We have demonstrated that there is a synergistic induction of cell death when we combine N3A/IR with Entinostat that is p53-dependent. In addition, we see that p53 acts as a barrier to genes associated with poor prognosis including FOXM1 which is phenocopied by single-agent Entinostat independent of WT-p53. This suppression may potentially be downstream of p21 via the DREAM complex. Importantly p53 mutation in TCGA primary PCa patients is associated with poor outcome and elevated FOXM1 expression.
Conclusion and Future Work
Results to date suggest that Entinostat enhances p53 dependent cell death but also has p53 dependent and independent mechanisms to suppress genes associated with poor prognosis PCa. The mechanism looks to be dependent of p21 and may involve DREAM complex.
Citation Format: Gemma M. Gregg, Fiammetta Falcone, Andrea Lees, Gerard Quinn, Peter Gallagher, Richard Kennedy, Ian I. Mills, Simon S. McDade. Investigating the effects of p53 activation and HDAC inhibition on genes associated with poor prognosis prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5425.
Abstract 5427: Inhibition of hypoxia-inducible factor 1 (HIF-1) transcriptional activity and cell mobility via G9a/GLP-mediated methylation of HIF-1α
Authors: Bao Lei , Chen Yan , Lai Hsien-Tsung , Chiang Cheng-Ming , Semenza Gregg L. , Wang Yingfei , Luo Weibo 
Published: August 2018

Abstract
Hypoxia-inducible factor 1 (HIF-1) is a main regulator of cellular response to hypoxia and its transcriptional activity is crucial for cancer cell migration and invasion. Post-translational modifications of the α subunit of HIF-1 (HIF-1α) play dominant roles in regulating its function. In this study, we demonstrated that the lysine methyltransferases G9a and GLP catalyzed mono- and di-methylation of HIF-1α at lysine (K) 674 in vitro and in vivo. Functionally, K674 methylation suppressed HIF-1 transcriptional activity as well as expression of the HIF-1 target genes including PTGS1, NDNF, SLC6A3, and Linc01132 in human glioblastoma U251MG cells. Moreover, mutation of K674 of HIF-1α significantly enhanced U251MG cell migration under hypoxia. Importantly, we found that G9a level was downregulated by hypoxia in glioblastoma, which was negatively correlated with PTGS1 expression and survival rate in glioblastoma patients. These findings reveal a novel naturally existing negative feedback mechanism that maintains high activity of HIF-1 and cell mobility in human glioblastoma.
Citation Format: Lei Bao, Yan Chen, Hsien-Tsung Lai, Cheng-Ming Chiang, Gregg L. Semenza, Yingfei Wang, Weibo Luo. Inhibition of hypoxia-inducible factor 1 (HIF-1) transcriptional activity and cell mobility via G9a/GLP-mediated methylation of HIF-1α [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5427.
Abstract 5428: Effect of amentoflavone on Nrf2 signaling in HaCaT cells
Authors: Wahyudi Lilik Duwi , Jeong Jiwon , Yang Heejung , Kim Jung-Hwan 
Published: August 2018

Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key mediator of cell response to oxidative stress and xenobiotics. Multiple lines of evidence suggest that Nrf2 activation protects against many diseases, aging, inflammation, and cancer. To date, Nrf2 activators from natural products have been widely studied. In this study we investigated the potential effect of Amentoflavone (AFN), a biflavonoid in many natural plants, on Nrf2 signaling in human keratinocytes cells (HaCaT). As results, AFN significantly increased ARE-luciferase activity and nuclear accumulation of Nrf2. Furthermore, a Nrf2 target protein, NQO-1, was significantly increased by AFN in dose- and time-dependent manner. To verify the Nrf2 signaling mechanism by AFN, firstly we measured reactive oxygen species (ROS) using DCFDA because mild intracellular ROS could stimulate Nrf2 activation. Surprisingly AFN triggered the production of ROS in 1 h and AFN-induced Nrf2 was inhibited by N-acetyl cysteine (NAC). Thus, we studied the ROS-related signaling on Nrf2 by measuring the activation of Akt and mitogen-activated protein (MAP) kinase family such as extracellular signal-regulated kinase (ERK) and p38. As results, pharmacology inhibitor of PI3K/Akt (LY294002) or p38 (SB 203580), but not ERK (U0126), abrogated AFN-activated Nrf2. Furthermore, silencing p38 using p38siRNA or inhibition using its pharmacology inhibitor decreased phosphorylation of Akt and attenuated Nrf2 activation. We also confirmed that AFN stabilized Nrf2 by inhibiting the ubiquitination. Taken together, AFN activates Nrf2 through ROS-mediated phosphorylation of p38 and followed by phosphorylation of Akt.
Citation Format: Lilik Duwi Wahyudi, Jiwon Jeong, Heejung Yang, Jung-Hwan Kim. Effect of amentoflavone on Nrf2 signaling in HaCaT cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5428.
Abstract 5433: XRCC5 promotes tumor growth and progression via PDK-1 signaling and predicts poor prognosis in melanoma
Authors: Qin Ge , Liu Tianze , Li Wenbin , Li Yixin , Zhang Changlin , Long Qian , Shi Dingbo , Chen Miao , Huang Shuting , Deng Wuguo 
Published: August 2018

Abstract
Melanoma is one of the most malignant and aggressive cancers with high cancer-related deaths. Patients with melanoma are often diagnosed at an advanced stage that has developed local or even remote metastasis due to its inapparent symptoms at early stages. Melanoma is often insensitive to chemotherapies, and most patients that respond well to targeted therapies or immunotherapies at first will develop resistance within several months. Therefore, it is of urgency to better understand the mechanisms of melanoma tumorigenesis, and to discover novel molecular targets for its effective treatment. In this study, we identified XRCC5 as a potential therapeutic target by siRNA library screening in A375 melanoma cells. We found that knockdown of XRCC5 inhibited cell growth, migration and invasion, and induced apoptosis in melanoma cells. Conversely,overexpression of XRCC5 significantly promoted the growth, migration and invasion of melanoma cells. We next analyzed the global transcriptome in A375 cells with XRCC5 knockdown, and identified PDK-1 as a candidate gene regulated by XRCC5. Further investigation revealed that XRCC5 cooperated with HIF-1α to bind at the promoter of PDK-1, and enhanced the expression of PDK-1. Consistently, overexpression of PDK-1 rescued the cell growth inhibition caused by XRCC5 knockdown. Our clinical data showed that the expression of XRCC5 and PDK-1 were positively correlated and elevated in melanoma samples, and high expression of XRCC5 predicted poor prognosis in melanoma patients. Collectively, our study discovered that XRCC5 bound to the promoter of PDK-1 to activate its expression, which promoted melanoma growth and progression. Our results indicated that the XRCC5/PDK-1 pathway could be a potential therapeutic target for melanoma.
Citation Format: Ge Qin, Tianze Liu, Wenbin Li, Yixin Li, Changlin Zhang, Qian Long, Dingbo Shi, Miao Chen, Shuting Huang, Wuguo Deng. XRCC5 promotes tumor growth and progression via PDK-1 signaling and predicts poor prognosis in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5433.
Abstract 5444: APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model
Authors: jin Guoguo 
Published: August 2018

Abstract
Esophageal cancer (EC) is one of the most aggressive malignancies of the upper aerodigestive tract. Over the past three decades, with advances in surgical techniques and treatment, the prognosis of esophageal cancer has only slowly improved. Thus identifying novel molecular targets and developing therapeutic agents are critical. Aurora kinases play a crucial role in mitosis and selective inhibitors might provide an effective therapeutic treatment for cancer. However, the role of Aurora kinases in EC is still inadequately studied. Here, we identified a novel compound, referred to as APIO- EE-9, which inhibits growth and colony formation and induces apoptosis of esophageal cancer cells. Using computer modeling, we found that APIO-EE-9 interacted with both Aurora A and B in the ATP-binding pocket. APIO-EE-9 inhibited both Aurora A and B kinase activities in a dose-dependent manner. Treatment with APIO-EE-9 substantially reduced the downstream Aurora kinase phosphorylation of histone H3 (Ser10), resulting in formation of multiple nuclei and centrosomes. Additionally, esophageal cancer cells expressing shAurora A or shAurora B kinase exhibited a dramatic reduction in proliferation and colony formation. Injection of these cells as xenografts in mice reduced tumor formation compared to wildtype cells. Importantly, APIO-EE-9 significantly decreased the size of esophageal patient-derived xenograft (PDX) tumors implanted in SCID mice. These results demonstrated that APIO-EE-9 is a specific Aurora kinase inhibitor that could be developed as a therapeutic agent against esophageal cancer.
Citation Format: Guoguo jin. APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5444.
Abstract 5452: Pimozide suppresses the growth of brain tumor by targeting oncogenic pathways
Authors: Kaushik Itishree , Ranjan Alok , Schwettmann Blake , Srivastava Sanjay 
Published: August 2018

Abstract
Brain tumor is considered as one of the most aggressive and incurable form of cancer. Majority of the brain tumors have a median survival rate of only 12%. Even though advanced treatments such as surgical removal, chemotherapy and radiotherapy are available, brain tumor persists to be lethal. Obstacles associated with the current treatment options are: recurrence, development of resistance and inability to cross blood brain barrier (BBB). BBB restricts majority of drugs to reach the brain thus resulting in an ineffective treatment. Pimozide (PMZ) is an antipsychotic drug used for the treatment of schizophrenia and chronic psychosis. In this study, pimozide has shown significant reduction in the viability of U-87MG, U-251MG, DAOY and T98G cell lines with an IC50 ranging from 11µM to 20µM after 24 h of treatment. Pimozide induced apoptosis in these cell lines as evaluated by FITC/Annexin assay and further validated by the cleavage of caspase 3 as well as PARP by western blot analysis. Pimozide treatment resulted in the concentration dependent decrease in the expression of GLI1, OCT4, SOX2 and NANOG in U87MG, U251MG, DAOY and T98G brain cancer cell lines, depicting a reduction in the stem cell like property of these cell lines. In addition, pimozide treatment inhibited the expression of proto-oncogene c-Myc. Inhibition of Gli1 and c-Myc demonstrates that pimozide might also inhibit the growth of cancer cells by targeting SHH signaling. Our results further demonstrated that oral administration of pimozide (25mg/kg) inhibits the brain tumors in intracranial tumor model with no significant difference in average weight of critical organs. It is important to note that pimozide is an FDA approved drug with no considerable toxicity. Overall, this study depicts that pimizode is a potential candidate to target brain tumors.
Citation Format: Itishree Kaushik, Alok Ranjan, Blake Schwettmann, Sanjay Srivastava. Pimozide suppresses the growth of brain tumor by targeting oncogenic pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5452.
Abstract 5462: Functional characterization of potential gain-of-function p53 mutants in esophageal squamous cell carcinoma
Authors: Yu Valen Z. , Lung Maria L. 
Published: August 2018

Abstract
One of the most frequently mutated genes reported in human cancers is TP53. Esophageal squamous cell carcinoma (ESCC) has an extremely high frequency of p53 mutations of 60-90% in ESCC patients. Evidence of gain-of-function (GOF) p53 mutations that exert wild-type (WT) function-independent oncogenic effects are emerging. We aim to determine the functional role of several candidate GOF p53 mutations in ESCC and explore their clinical utility for prognostication and as potential treatment targets. In our recent study of Hong Kong ESCC specimens, we detected TP53 alterations in over 90% of ESCC tumors, ~36% of which are candidate GOF mutations verified in other cancers. By analyzing published ESCC sequencing data, we showed that patients from the high-risk ESCC region show frequent candidate GOF p53 mutants. We applied the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technique to functionally knockout (fKO) mutant p53 protein expression in various ESCC cell lines with different endogenous p53 mutants and subject them to in vivo and in vitro functional assays. Interestingly, only KYSE150 cells with an endogenous p53R248Q mutation show reduced tumor growth in nude mice after p53-fKO, suggesting that there is a specific mutant p53 that confers oncogenic features in ESCC. Consistently, only KYSE150 p53-fKO cells show reduced colony formation in three-dimension in vitro culture. Tyrosine phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) is significantly reduced in KYSE150 p53-fKO cells, suggesting that regulation of the STAT3 pathway contributed to the oncogenic feature of the GOF p53 mutant. p53R248Q exhibits concentrated subcellular localization to the membrane fraction (including ER, mitochondria, etc.) and shows increased resistance to HSP90/HDAC inhibition-induced protein degradation, as compared to other p53 mutants. Together, these results suggest a GOF role of certain mutant p53 proteins with specific characteristics. Targeting such mutants and/or related oncogenic pathways may be of therapeutic benefit. Acknowledgement: We acknowledge the Research Grants Council of Hong Kong Special Administrative Region for General Research Fund support (17109515 to M.L.L).
Citation Format: Valen Z. Yu, Maria L. Lung. Functional characterization of potential gain-of-function p53 mutants in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5462.
Abstract 5466: CXCL14 suppresses the aggressive phenotype in triple-negative breast cancer (TNBC) through CXCR4
Authors: Gibbs Carla R. , Ignacio Rosa Mistica C. , Richmond Ann , Son Deok-Soo 
Published: August 2018

Abstract
The chemokine network is involved in cancer metastasis by modulating cell migration and angiogenesis. CXCL12-CXCR4 is a common signaling axis that is associated with cancer metastasis. Metastatic breast cancers often overexpress the CXCR4 receptor, whereas lung tissues express high levels of CXCL12; consequently, this is a proposed mechanism for breast cancer metastasis to the lung. CXCL14, an anti-inflammatory chemokine, has been postulated to be an alternative ligand for CXCR4, though a formal assignment of CXCR4 as the receptor for CXCL14 has not been made. Interestingly, CXCL14 competes with CXCL12, a main ligand for CXCR4, to modulate CXCL12-CXCR4 downstream activation of ERK. CXCL14 expression is downregulated in oral, colon, prostate, lung, pancreatic, cervical, kidney cancers, and in TNBC when compared to other subtypes of breast cancer. Overexpression of CXCL14 in cancer cell lines in vivo and in vitro leads to decrease in tumor metastasis. CXCL14 overexpression in the MDA-MB-231 breast cancer cell line leads to a decrease in cell growth, invasion and migration. To further explore a role for CXCL14 in breast cancer aggressiveness, we examined the effects of CXCL14 on the cell migration and metastasis of additional breast cancer cell lines. Here we performed cell migration and MTT cytotoxicity assays using MDA-MB-231 and BT-549 TNBC cell lines and the MCF-7 estrogen receptor+ cell line. Our results demonstrate TNBC cells are significantly more sensitive to CXCL14 compared to non-TNBC MCF7 cells (in Boyden chamber migration assay). Also, in our experiments CXCL14 did not alter proliferation in either TNBC cells or non-TNBC cells. However, when we generated CXCR4-overexpressing breast cancer cell lines using parental BT-549, MDA-MB-231, and MCF-7 cells, we observed the changes in the phosphorylation of ERK1/2 (MAPK targets) and pAKT (PI3K downstream effector protein). Based on these data, we propose CXCL14 as a negative modifier of the CXCL12-CXCR4 axis in TNBC. Based on these data, we propose a negative role for CXCL14 in the modulation of TNBC aggressiveness.
Citation Format: Carla R. Gibbs, Rosa Mistica C. Ignacio, Ann Richmond, Deok-Soo Son. CXCL14 suppresses the aggressive phenotype in triple-negative breast cancer (TNBC) through CXCR4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5466.