bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3438: Selective inhibitors of Mcl-1 with potent activity against multiple myeloma patient cells and animal xenografts.
Authors: Azmi Asfar S. , Nikolovka-Coleska Zaneta , Abidi Muneer , Marsack Kelley , Masood Ashiq , Yano Hiroshi , Pregja Silvana , Zonder Jeffrey , Mohammad Ramzi M. 
Published: August 2014

Abstract
To date most of the studies targeting apoptotic machinery have focused on inhibiting Bcl2 and BclXL proteins that have shown limited clinical utility. This could be in part due to the over-expression of Myeloid Leukemia-1 (Mcl-1) that carries similar anti-apoptotic functions. Our recent evaluations of Multiple Myeloma (MM) patient derived samples have shown consistent over-expression of Mcl-1 suggesting that it is an attractive therapeutic target. We have discovered a novel druggable site in Mcl-1 protein. Using structure based drug design we have developed small molecule inhibitors (SMIs) of Mcl-1 that bind with high affinity to the BH-3 hydrophobic groove of the protein thereby displacing different pro-apoptotic partners such as Bax, Bak, Bok and Bid with activity against MM cells (IC50 5 μM) and anti-tumor activity in animal xenografts. The lead SMI (UMI-77) inhibits growth and induces apoptosis in MM cells. Molecular analysis of MM cells reveals activation of pro-apoptotic factors post UMI-77 treatment. Co-immunoprecipitation studies show that UMI-77 disrupts the Mcl-1-Bax and Mcl-1-Bak interactions. The drug synergizes with standard proteasome inhibitor Velcade (5 nM) and Carfilosimib (1 nM). In patient derived MM cells (n=45), UMI-77 inhibits growth and induces apoptosis that is concurrent with induction of Bax, Bak and enhancement in cleaved fractions of caspases 3 and 9. At similar concentrations UMI-77 does not affect normal peripheral lymphocytes. UMI-77 is well tolerated by animals at MTD (60 mg/kg i.v.). In a mice lymphoma model, oral administration of UMI-77 significantly reduced tumor growth and histological examination of tumors revealed suppression of Mcl-1 protein expression along with enhancement of pro-apoptotic markers. Our novel Mcl-1 inhibitors provide a new therapeutic option for cancers for MM that overexpress Mcl-1 that have failed standard therapies.
Citation Format: Asfar S. Azmi, Zaneta Nikolovka-Coleska, Muneer Abidi, Kelley Marsack, Ashiq Masood, Hiroshi Yano, Silvana Pregja, Jeffrey Zonder, Ramzi M. Mohammad. Selective inhibitors of Mcl-1 with potent activity against multiple myeloma patient cells and animal xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3438. doi:10.1158/1538-7445.AM2013-3438
Abstract 3447: Obatoclax analogue SC-2001 induced autophagy through SHP1/STAT3 pathway in hepatocelluar carcinoma.
Authors: Su Jung-Chen , Liu Chun-Yu , Tai Wei-Tien , Chen Kuen-Feng , Shiau Chung-Wai 
Published: August 2014

Abstract
Obatoclax induced cancer cells apoptosis through targeting anti-Bcl-2 family. Previously, we have generated 20 obatoclax analogues with three synthetic steps and tested cytotoxicity in HCC cell lines. Among these analogues, SC-2001 not only inhibited anti-Bcl-2 family activity but also reduced STAT3 phosphorylation and subsequently repressed transcriptional activity of STAT3 targeting genes. Here, we further revealed that SC-2001 induced LC3-II with time and dose dependent manner in HCC cell line. We also observed that autophogosomes were induced with SC-2001 treated cells under electron microscope detection. Conversely, sodium vanadate, a phosphatase inhibitor, abolished the LC3 induction and autophagic effect in SC-2001 treated cells. In addition, overexpression of STAT3 in PLC5 cells attenuate autophagic effect with SC-2001 treatment. Genetic knockdown of SHP-1, a negative regulator of STAT3, by siRNA reduced autophagy induced by SC-2001. In summary, our data suggested that SC-2001 can induce autophagic cell death through, at least in part, SHP-1/STAT3 signaling pathway. (Supported by NSC-100-2325-B-010-007)
Citation Format: Jung-Chen Su, Chun-Yu Liu, Wei-Tien Tai, Kuen-Feng Chen, Chung-Wai Shiau. Obatoclax analogue SC-2001 induced autophagy through SHP1/STAT3 pathway in hepatocelluar carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3447. doi:10.1158/1538-7445.AM2013-3447
Abstract 3451: Gramicidin-based nanopores induce cellular energy depletion and cell death in renal cell carcinoma.
Authors: David Justin M. , Rajasekaran Ayyappan K. 
Published: August 2014

Abstract
The plasma membrane physically separates the intracellular components of a cell from the extracellular environment and its integrity is absolutely essential to sustain cellular functions. Ionophores are lipid soluble organic molecules that disrupt cellular transmembrane potential by rendering biological membranes permeable to specific ions. They are classified on the basis of their mechanism of action; mobile carriers complex with metal cations to shield their hydrophilic charge from the interior of the lipid bilayer and channel-formers insert into the membrane to form hydrophilic pores that permit the rapid passage of selected ions through membranes. Research over the past decade has described an new role for mobile carrier ionophores as novel anticancer therapeutics yet the potential anticancer attributes of channel-forming ionophores have not been explored. In this study we utilized the channel-forming ionophore gramicidin A (GA) as a model nanopore to study its effects upon the growth and survival of renal cell carcinoma (RCC) cells. RCC is a histologically heterogeneous malignancy that is highly resistant to conventional chemotherapy. We found that disruption of plasma membrane integrity with GA reduced the in vitro viability of several RCC cell lines when treated at sub-micromolar concentrations (all IC50 &lt; 1.0μM). Comparison of GA with the mobile carrier ionophore monensin revealed that cell viability was decreased by GA to a degree that was equal to or greater than monensin depending on the cell line. Mechanistic examination determined that GA induced cell death that was associated with cellular energy depletion. Importantly, GA exhibited similar toxicity in RCC cells regardless of histological subtype or the expression of either the von Hippel-Lindau (VHL) tumor suppressor or its downstream target hypoxia-inducible factor (HIF) -1α. Taken together, these results demonstrate the utility of nanopore-forming drugs as a new strategy for cancer therapy.
Citation Format: Justin M. David, Ayyappan K. Rajasekaran. Gramicidin-based nanopores induce cellular energy depletion and cell death in renal cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3451. doi:10.1158/1538-7445.AM2013-3451
Abstract 3562: Genome-wide analysis of the vitamin D receptor (VDR) binding sites reveals vitamin D role modulating autophagy and metabolism in luminal-like breast cancer cells.
Authors: Tavera Luz E. , Westerling Thomas , Brown Myles 
Published: August 2014

Abstract
The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), regulates gene expression through the vitamin D receptor (VDR). Even though 1,25D3 is still best known as a regulator of bodily calcium homeostasis, 1,25D3 has a plethora of physiological actions which include immune and nervous system modulation, cellular proliferation and differentiation. Epidemiological and model studies have revealed the cancer-protective properties of 1,25D3 in colon, prostate and notably in breast. We are actively investigating the anti-proliferative properties of 1,25D3 in a panel of human breast cancer cell lines. We found that 1,25D3 induces autophagy in several luminal-like breast cancer cell models, but not in basal-like or mesenchymal-like models. We performed VDR and signaling partner RXR whole-genome ChIP-seq analysis to uncover all of the direct 1,25D3 target genes involved in regulation of metabolism and autophagy. Our studies suggest that energy regulation as an important aspect of 1,25D3 anti-proliferative properties in luminal-like breast cancer cells.
Citation Format: Luz E. Tavera, Thomas Westerling, Myles Brown. Genome-wide analysis of the vitamin D receptor (VDR) binding sites reveals vitamin D role modulating autophagy and metabolism in luminal-like breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3562. doi:10.1158/1538-7445.AM2013-3562
Abstract 410: Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers.
Authors: Zhu He , Zhou Xinchun , Redfield Samantha , Lewin Jack , Miele Lucio 
Published: August 2014

Abstract
Background: Emerging evidence has suggested that Notch signaling pathway may be involved in the development, progression and metastasis of prostate cancer (PCa). In the present study, we investigated the expression levels of Jagged-1 and Notch-1 in human prostate tumors and their associations with prostate cancer progression and metastasis.
Methods: Immunohistochemistry (IHC) for Jagged-1 and Notch-1 was performed on tissue microarray (TMA) slides containing 286 formalin-fixed and paraffin-embedded tissue specimens with various prostatic disorders, including benign changes, high grade prostatic intraepithelial neoplasia (HGPIN), low and high grade prostate cancers as well as metastatic prostate cancers. The expression levels of Jagged-1 and Notch-1 were reported as a final IHC score calculated as staining extent score (0-3) multiplied by intensity score (0-3); with a maximal score equal to 9. ANOVA and t-test were employed to analyze the difference of IHC scores among and between different pathologic categories
Results: Jagged-1 cytoplasmic IHC scores in both metastatic PCa (5.92 ± 2.12, Mean ± SD) and high grade PCa (5.74 ± 2.45) were significantly higher than those in low grade PCa (3.55 ± 2.02, p = 9.02E-07 and 4.65E-08, respectively), in HGPIN (4.50 ± 2.34, p = 0.023 and 0.030, respectively), and in prostatic tissues with benign changes (3.39 ± 1.85, p = 7.96E-07 and 2.47E-07, respectively). In addition, Jagged-1 membranous IHC scores in both metastatic PCa (3.05 ± 3.52) and high grade PCa (2.41 ± 2.90) were also significantly higher than those in low grade PCa (0.71 ± 1.42, p = 1.48E-05 and 3.40E-06, respectively) and in prostatic tissues with benign changes (0.82 ± 1.28, p = 3.19E-04 and 0.001, respectively). Similarly, Notch-1 cytoplasmic IHC scores in both metastatic PCa (2.22 ± 2.11) and high grade PCa (1.10 ± 1.68) were significantly elevated when compared with the IHC scores observed in low grade PCa (0.51 ± 1.15, p = 3.63E-06 and 0.023, respectively) and in prostate tissues with benign changes (0.48 ± 1.01, p = 3.37E-06 and 0.017, respectively). Furthermore, significantly more highly expressed Jagged-1 in membrane was observed in Caucasians (vs. African Americans) and in positive surgical resection margin group (vs. negative surgical resection margin group).
Conclusions: Our results provide strong evidence that dysregulation of Jagged 1-Notch1 signaling plays a role in PCa progression and metastasis and suggest that Jagged-1 and Notch-1 may be useful markers in distinguishing indolent and aggressive prostate cancers.
Citation Format: He Zhu, Xinchun Zhou, Samantha Redfield, Jack Lewin, Lucio Miele. Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 410. doi:10.1158/1538-7445.AM2013-410
Abstract 4181: Oncogenic microRNA-183 induces cell growth and motility through down-regulation of Dkk-3 and SMAD4 in bladder cancer.
Authors: Ueno Koji , Hirata Hiroshi , Shahryari Varahram , Tanaka Yuichiro , Tabatabai Z. Laura , Hinoda Yuji , Dahiya Rajvir 
Published: August 2014

Abstract
Introduction and Objective : The purpose of this study was to carry out functional analysis of oncogenic microRNA-183 and identify their specific target genes in bladder cancer.
Methods : Expression levels of miR-183 in bladder normal/cancer tissues and bladder cancer cell lines were confirmed using real-time PCR. To examine the function of miR-183, cell growth, and migration were performed using UM-UC-3 cells because the miR-183 expression level was highest among bladder cancer cell lines. To search for target genes of miR-183, we used a target scan algorithm and performed Dkk-3 and SMAD4 3’UTR luciferase assays. To analyze whether Dkk-3 and SMAD4 affect cell growth and motility, Dkk-3 and SMAD4 expressing plasmids were transfected into UM-UC-3 cells and cell growth and motility were performed.
Results: Expression of miR-183 in cancer bladder tissues was significantly up-regulated compared to normal bladder tissues. MiR-183 expression was significantly higher in the pT3+4 tissues than in pT1+2 tissues. Higher miR-183 expression was significantly associated with shorter survival. MiR-183 increased cell growth and migration abilities in UM-UC-3 cells. MiR-183 decreased 3’UTR luciferase activity of Dkk-3 and SMAD4. Cell growth and motility was significantly decreased in Dkk-3 and SMAD4 transfected cells compared with control cells.
Conclusions : MiR-183 is a oncogenic microRNA in bladder cancer through down-regulation of Dkk-3 and SMAD4.
Citation Format: Koji Ueno, Hiroshi Hirata, Varahram Shahryari, Yuichiro Tanaka, Z. Laura Tabatabai, Yuji Hinoda, Rajvir Dahiya. Oncogenic microRNA-183 induces cell growth and motility through down-regulation of Dkk-3 and SMAD4 in bladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4181. doi:10.1158/1538-7445.AM2013-4181
Abstract 4186: miR-218 suppresses invasion and migration via inhibition of ZEB2 and N-Cadherin in colon cancer.
Authors: Batliner Jasmin , Abba Mohammed , Hauser Christine , Allgayer Heike 
Published: August 2014

Abstract
The great majority of cancer deaths are due to metastasis. A hallmark of cancer metastasis is the process of epithelial to mesenchymal transition (EMT), in which cells alter their gene expression program resulting in loss of their epithelial characteristics and gain of typical mesenchymal properties. Recently, microRNAs have been shown to play key roles in the dynamic process of EMT, orchestrating a coordinated multi-target repression of genes and, together with master transcription factors, act in regulatory networks to alter cell function. We used a miRNA-microarray platform to identify differentially expressed microRNA genes in primary tumor, distant metastatic and corresponding normal samples in a cohort of resected patient tissues. From our list of differentially regulated microRNAs we focused on miR-218 as so far very little information has been accumulated regarding its function in cancer. In our microarray analysis, miR-218 was significantly downregulated in tumor/metastatic tissue compared to normal colon tissue. We validated miR-218 expression in an additional series of 42 colorectal cancer patient tissues, where we found a significant downregulation of miR-218 in tumor as compared to the corresponding normal tissues in over 80% of cases. Furthermore, ectopic expression of miR-218 significantly reduced in vitro invasion and migration of invasive colorectal cancer cell lines and upregulated the key epithelial marker E-cadherin, while silencing of miR-218 lead to enhanced migration and invasion. In addition, we identified two novel miR-218 target genes that are associated with EMT including ZEB2, a zinc-finger transcription factor, and N-Cadherin, using reporter gene, RT-PCR and Western blot analysis. In our present study, we show that miR-218 is a direct suppressor of EMT by its ability to downregulate ZEB2 and N-Cadherin expression and represents an additional molecule contributing to the complexity of the EMT regulatory network.
Citation Format: Jasmin Batliner, Mohammed Abba, Christine Hauser, Heike Allgayer. miR-218 suppresses invasion and migration via inhibition of ZEB2 and N-Cadherin in colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4186. doi:10.1158/1538-7445.AM2013-4186
Abstract 4279: Isolation of a high affinity, specific human monoclonal antibody that binds to FGFR-2 IIIc.
Authors: Schwertschlag Ullrich S. , Turner Katherine J. ,   Central Lab Naval Hospital Bejing.
Published: August 2014

Abstract
Fibroblast Growth Factor Receptor-2 (FGFR-2) expression and activation have been increasingly implicated in a number of human cancers, including prostate, ovarian, breast, gastric, bladder, pancreatic, endometrial and lung malignancies. Mechanisms include stimulation of angiogenesis, direct stimulation of tumor growth and promotion of tumor metastasis. Similar to other FGFRs, FGFR-2 binds a subset of FGF ligands with high affinity and consists of an extracellular region comprised of two or three immunoglobulin-like (Ig) domains, a single transmembrane region and an intracellular kinase domain. Variable splicing in the second half of the third Ig-like domain generates two isoforms, IIIb or IIIc, with different ligand binding specificity and expression patterns. An isoform switch from epithelial cell-expressed FGFR-2IIIb to mesenchymal cell-expressed FGFR2-IIIc has been shown to associate with an epithelial to mesenchymal transition (EMT), which increases cell migration and invasion and facilitates metastasis of epithelial carcinomas, such as prostate and bladder cancer. Several groups are developing antibodies to block FGFR-2 as therapeutics. Small molecule drugs that block FGFR-2 signaling are currently being evaluated in clinical trials. Recently, there have been reports of FGFR-2 IIIb-specific antibodies. In the same studies, monoclonal antibodies that bind both isoforms IIIb and IIIc were described, but, to date, no detailed studies describing the isolation of an FGFR-2 IIIc-specific antibody have been reported. The high degree of sequence conservation between the IIIb and IIIc exons is presumably the major reason why this has been technically challenging. In this study, we report the isolation of a high affinity, human monoclonal antibody, ATTO-1, and a murine mAb, 5H11, that bind to human and mouse FGFR-2 IIIc, but not FGFR2-IIIb, respectively. ATTO-1 binds to established mesenchymal tumor cell lines, such as AT3 and BT459 (FGFR-2 IIIc+), but not to MCF-7 or DT (FGFR-2 IIIb+). These antibodies may be valuable research tools for studying and developing novel therapies for blocking tumor invasion and metastasis.
Citation Format: Ullrich S. Schwertschlag, Katherine J. Turner, Central Lab Naval Hospital Bejing. Isolation of a high affinity, specific human monoclonal antibody that binds to FGFR-2 IIIc. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4279. doi:10.1158/1538-7445.AM2013-4279
Abstract 4305: FBXO31 functions as an oncoprotein by suppressing apoptosis via regulation of MAPK pathway in esophageal squamous cell carcinoma cell lines.
Authors: Liu Jia , Li Bin , Tsao George SW , Cheung Annie ML 
Published: August 2014

Abstract
FBXO31 is a DNA-damage responsive F-box protein, found to be down-regulated in breast and hepatocellular carcinoma but up-regulated in esophageal squamous cell carcinoma. The role of FBXO31 in carcinogenesis is not fully determined. Mitogen activated protein kinases (MAPKs) play pivotal role in cellular response to diverse stresses, and are involved in regulating cell proliferation, differentiation and apoptosis. In this study, data from gain-of-function and loss-of-function experiments revealed that FBXO31 regulated cell apoptosis upon UV stress, as evidenced by changes in expressions of cleaved caspase 3 and PARP in FBXO31 modified cell lines compared to control cell lines, as well as regulation of sub-G1 population measured by flow cytometry analysis. The effects of FBXO31 on apoptosis were associated with changes in MAPK p38 and JNK phosphorylation. In order to verify the role of FBXO31 in cell apoptosis and MAPK regulation, shRNA rescue experiments were performed. The results showed that ectopic overexpression of wild type FBXO31 in stable cell line which expressed shRNA targeting the 3’ UTR of FBXO31 could reverse the effects of FBXO31-knockdown on apoptosis, and on MAPK p38 and JNK phosphorylation. Furthermore, we found that JNK was a dominant mediator of FBXO31 in regulating cell apoptosis upon UV stress since treatment with JNK inhibitor, but not p38 inhibitor, reversed apoptosis induced by FBXO31-knockdown. Consistent with this finding, soft agar assay and in vivo xenograft experiments showed that knockdown of FBXO31 reduced the tumorigenic potential of ESCC cells. In conclusion, our data suggest that FBXO31 functions as an oncogenic protein in ESCC by suppressing cell apoptosis via MAPK pathway. This mechanism may favor the survival of tumor cells in stringent environment and contribute to ESCC development.
Citation Format: Jia Liu, Bin Li, George SW Tsao, Annie ML Cheung. FBXO31 functions as an oncoprotein by suppressing apoptosis via regulation of MAPK pathway in esophageal squamous cell carcinoma cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4305. doi:10.1158/1538-7445.AM2013-4305