bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5237: Targeting DCN1-mediated neddylation in lung SCC with novel small-molecule inhibitors
Authors: Barrios Richard , Hammill Jared , Min Jaeki , Guy Kip 
Published: July 2017

Abstract
Due to the anti-neoplastic properties and clinical successes of the proteasome inhibitors Bortezomib and Carfilzomib, the ubiquitin-proteasome system (UPS) has become a new target of interest in oncology research. The clinical toxicity induced by these inhibitors, likely caused by complete inhibition of the UPS, has resulted in a need for the development of more selective UPS regulators. A more in depth understanding of the intrinsic molecular mechanisms that are associated with the UPS has unmasked the potential for improved therapies via more specific targets such as the process of neddylation, which is thought to control 15 - 20% of the UPS (5). During neddylation, an enzyme known as DCN1 for “defective in cullin neddylation 1” functions as a co-E3 to help steer a ubiquitin-like protein (UBL), NEDD8, from an E2 enzyme, UBC12, to a cullin (CUL) neddylation site (6 - 7, 9 - 11). Because DCN1 has been found to be amplified in certain squamous cell carcinomas (9) (SCCs; e.g. lung, esophagus, and head and neck), this in vitro, pre-clinical study demonstrates the potential of the DCN1-UBC12 interaction as a therapeutic site in lung SCCs through the use of novel small-molecule inhibitors from the St. Jude (SJ) library. After optimizing dosing regimens, it has been determined that re-administering the SJ compounds (i.e. SJ690, SJ447, SJ446, and SJ323) every 24-hours to address the issue of protein turn-over, produces more efficacious treatment. The most biochemically-potent antagonists in the compound series were also shown in these primary cell lines to potentiate other therapeutic agents such as Cisplatin; however, these compounds alone do not induce DNA damage, nor do they elicit caspase 3/7 activity. Nonetheless, combination treatment of the SJ compounds with Staurosporine in SCC cell lines, potentiated caspase 3/7 activity at varying degrees. Collectively, this data enhances our understanding of the mechanism by which the inhibition of DCN1 affects cancer cells, informing pre-clinical development of the SJ DCN1 antagonists.
Citation Format: Richard Barrios, Jared Hammill, Jaeki Min, Kip Guy. Targeting DCN1-mediated neddylation in lung SCC with novel small-molecule inhibitors [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 5237. doi:10.1158/1538-7445.AM2017-5237
Abstract 5240: Induction of molecular endpoints by reactive oxygen species in human lung cells predicted by physical- chemical properties of engineered nanoparticles
Authors: Ross Jeffrey A. , Nelson Garret B. , Jones Carlton , Thai Sheau-Fung 
Published: July 2017

Abstract
A series of six titanium dioxide and two cerium oxide engineered nanomaterials were assessed for their ability to induce cytotoxicity, reactive oxygen species (ROS), and various types of DNA and protein damage in human respiratory BEAS-2B cells exposed in vitro for 72 hours at several concentrations. Although only limited cytotoxicity was observed at concentrations up to 300 µg/ml for all of the nanomaterials, significant increases in 8-oxo-deoxyguanosine, lipid peroxidation mediated protein adducts, and endogenous DNA adducts measured by 32P-postlabeling were detected at concentrations as low as 30 µg/ml, suggesting that molecular changes associated with ROS induction may provide a better means of assessing the low-dose hazards posed by nanomaterials. To identify molecular properties predictive of the ability of nanoparticles to induce ROS sequelae, a least absolute shrinkage and selection operator multiple regression approach has been used to identify relationships between assay outcomes and nanoparticle physical/chemical properties, including particle size, surface area, zeta potential, and elemental analysis. For several of the assay endpoints examined, concentrations of trace metals in the nanoparticles appear to be better predictors of assay outcomes than physical properties. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.
Citation Format: Jeffrey A. Ross, Garret B. Nelson, Carlton Jones, Sheau-Fung Thai. Induction of molecular endpoints by reactive oxygen species in human lung cells predicted by physical- chemical properties of engineered nanoparticles [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 5240. doi:10.1158/1538-7445.AM2017-5240
Abstract 5245: Peretinoin prevents the accumulation of somatic gene mutations and reverts neoplastic lesions to normal liver-like in platelet-derived growth factor-c transgenic mice
Authors: Yamashita Taro , Okada Hikari , Honda Masao , Kaneko Shuichi 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) develops with progressive accumulation of multiple genetic changes. An acyclic retinoid peretinoin is reported to suppress the development of HCC, but the molecular mechanism in detail remains to be obscure. Here we evaluated the effect of peretinoin on preneoplastic nodules and HCC developed in platelet derived growth factor-c (PDGF-C) transgenic mice liver by gadolinium ethoxybenzyl diethylenetriamide pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and whole exome sequence analysis. We confirmed the progressive accumulation of somatic mutations in hypervascular liver cancer tissues compared with hypovascular precancerous tissues and non-cancerous background liver tissues in PDGF-C transgenic mice. Surprisingly, peretinoin treatment in HCC as well as preneoplastic nodules resulted in the accumulation of less gene mutations compared with vehicle. Gd-EOB-DTPA uptake capacity and its transporter OATP1 was confirmed to be re-activated in peretinoin treated nodules in mice. Gene and protein expression analysis indicated the inactivation of cell cycle with low Ki-67 labeling indexes in peretinoin treated nodules. The reversion of Gd-EOB-DTPA uptake capacity was confirmed in preneoplastic nodules and a subset of classical hypervascular HCCs. Notably, peretinoin supplementation induced the expression of OATP1B3 in mature hepatocyte-like HCC cell lines in vitro, whereas supplementation of tretinoin (all-trans retinoic acid) had no such effects and rather suppressed OATP1B3. Taken together, our data suggested the utility of peretinoin to revert the malignant transformation processes of hepatocytes by preventing accumulation of gene mutations especially in early stages of hepatocarcinogenesis. Peretinoin but not tretinoin can induce the expression of a mature hepatocyte marker OATP1B3, suggesting that peretinoin may exert its anti-tumor effect with hepatocytic differentiation capacity independently of the activation of retinoic acid signaling.
Note: This abstract was not presented at the meeting.
Citation Format: Taro Yamashita, Hikari Okada, Masao Honda, Shuichi Kaneko. Peretinoin prevents the accumulation of somatic gene mutations and reverts neoplastic lesions to normal liver-like in platelet-derived growth factor-c transgenic mice [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 5245. doi:10.1158/1538-7445.AM2017-5245
Abstract 5251: Amentoflavone regulate Hh-Gli1 signaling pathway and inhibits tumorsphere formation in U251 glioblastoma cells
Authors: Chen Jing , Bao Cheng , Lee Hong Jin 
Published: July 2017

Abstract
Cancer stem cells represent a rare population of cells with a self-renewal capacity, and potentially are involved in tumor progression, tumor relapse, and resistance to cancer chemotherapies. In this study, we investigated the effect of an active ingredient of chamaecyaris obtuse, amentoflavone, on stemness of U251 glioblastoma cells. We first found that amentoflavone from 1 to10 μM suppressed tumorsphere formation and inhibited the expression of glioblastoma stem cell markers CD133 and ALDH1 in a dose dependent manner. In addition, amentoflavone significantly reduced the expression of Nanog involved in cancer stem cells maintenance in tumorsphere culture. As an upstream modulator, Hedgehog (Hh) signaling mediator Gli1 was confirmed to be highly expressed in tumorsphere culture where the suppression of Gli1 by the treatment of Hh inhibitors (vismodegib and GANT 61) or Gli1-siRNA significantly suppressed the expression of stem cell markers CD133, ALDH1, and Nanog as well as tumorsphere formation in U251 glioblastoma cells. These results indicate that Hh signaling plays an important role in maintaining tumorsphere and stemness of U251 glioblastoma cells. Next, we also found that the treatment of amentoflavone from 1 to10 μM inhibited the expression of Gli1 and its downstream mediator Nanog in tumorsphere culture of U251 glioblastoma cells. Taken together, amentoflavone significantly suppressed Hh/Gli1 signaling which results in inhibition of stemness of U251 glioblastoma cells.
Citation Format: Jing Chen, Cheng Bao, Hong Jin Lee. Amentoflavone regulate Hh-Gli1 signaling pathway and inhibits tumorsphere formation in U251 glioblastoma 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 5251. doi:10.1158/1538-7445.AM2017-5251
Abstract 5253: Arctigenin inhibits prostate tumor growth in vitro and in vivo in obese state
Authors: Wang Piwen , Diaz Tanya , Henning Susanne , Vadgama Jaydutt 
Published: July 2017

Abstract
Arctigenin is a novel anti-inflammatory lignan derived mainly from the seeds of Arctium lappa which is an herb widely used in traditional Chinese medicine to treat inflammation related diseases. We previously demonstrated that arctigenin strongly inhibited prostate tumor cell growth in cell culture and mouse models in non-obese state. The present study investigated the tumor inhibitory effect of arctigenin in obese state. An in vitro obese setting was created by co-culture of mouse adipocytes 3T3-L1 with androgen-sensitive LAPC-4 and LNCaP prostate cancer cells. An ELISA analysis of 3T3-L1 conditioned medium revealed that three cytokines/growth factors were prominently secreted by 3T3-L1 cells, including IGF-1, VEGF, and MCP-1, and the sensitivity of prostate cancer cells to arctigenin was decreased in the obese state. However, arctigenin at a moderate concentration (10 µM) significantly inhibited the proliferation of both LAPC-4 and LNCaP cell by 40-50% at 96h in the co-culture system. Male severe combined immunodeficiency (SCID) mice was implanted subcutaneously with LAPC-4 xenograft tumors to confirm the tumor-inhibitory effect of arctigenin in vivo. Mice were fed high-fat diet containing 45% energy from fat, and treated with arctigenin at 50mg/kg b.w. orally or vehicle control for 6 weeks (n=10 per group). The tumor growth in arctigenin group was significantly inhibited by 40% compared to control, along with decreased blood concentrations of several cytokines including IGF-1, VEGF, and MCP-1. Immunohistochemistry analysis is ongoing to determine the molecular changes involved in tumor cell proliferation and apoptosis in response to arctigenin treatment. This study provides a promising natural compound to enhance chemoprevention of prostate cancer especially in obese patients. These results warrant future clinical trial studies to confirm the anti-carcinogenic effect of arctigenin in humans.
Citation Format: Piwen Wang, Tanya Diaz, Susanne Henning, Jaydutt Vadgama. Arctigenin inhibits prostate tumor growth in vitro and in vivo in obese state [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 5253. doi:10.1158/1538-7445.AM2017-5253
Abstract 5258: Benzyl isothiocyanate prevents breast cancer-induced bone erosion in vivo
Authors: Pore Subrata K. , Singh Shivendra V. 
Published: July 2017

Abstract
Bone is one of the metastatic sites for advanced breast cancer. Nearly 70% of breast cancer patients experience metastasis to bone due to enhanced osteoclastogenesis and formation of osteoclasts leading to bone resorption. We have shown previously that benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables such as garden cress, is a potent inhibitor of breast cancer cells in vitro and in vivo. The present study was designed to determine the effect of BITC on breast cancer-induced osteoclastogenesis. Co-culture of murine RAW 264.7 macrophages with human breast cancer cells resulted in genesis of osteoclasts in vitro that was suppressed significantly in the presence of BITC. Runx2, a transcription factor, is abnormally expressed in breast cancer and contributes to osteoclastogenesis by regulating receptor activator of NF-κB ligand (RANKL). BITC treatment downregulated expression of Runx2 in breast cancer cells at the mRNA and protein levels. Osteoclastogenesis was increased in Runx2 overexpressing MDA-MB-231 cells, whereas conditional knockdown of Runx2 in T47D cells attenuated this process. To determine the in vivo efficacy of BITC, MDA-MB-231-Luc cells were injected into the left ventricle of nude mice. BITC was administrated orally at 10 mg per kg body weight. Micro-CT X-ray analysis showed that bone metastases and erosion was decreased by about 50% upon BITC treatment when compared with vehicle control. Cathepsin K and total RANKL levels were lower in the plasma of BITC-treated mice when compared to the control group. Altogether, this study demonstrates, for the first time, that BITC is a potent inhibitor of breast cancer-induced osteoclastogenesis in vivo. This study was supported by the grant RO1 CA129347-09 awarded by the national Cancer Institute.
Citation Format: Subrata K. Pore, Shivendra V. Singh. Benzyl isothiocyanate prevents breast cancer-induced bone erosion in vivo [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 5258. doi:10.1158/1538-7445.AM2017-5258
Abstract 526: NFκB p65 overexpression promotes bladder cancer migration via FBW7-mediated degradation of RhoGDIα protein
Authors: Li Yang , Zhu Junlan , Li Jingxia , Huang Chuanshu 
Published: July 2017

Abstract
Since bladder cancer (BC) is one of the most lethal urological malignant tumors worldwide, understanding the molecular mechanisms that trigger the migration, invasion and metastasis of BC has great significance in reducing the mortality of this disease. RelA/p65, a member of the NF-kappa B transcription factor family, is increasingly recognized as a crucial player in many steps of cancer initiation and progression. In this study, we unexpectedly found that p65 protein expression increased in the bladder carcinogen N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced high invasive bladder tumor tissues, and in human bladder cancer cell lines. We also observed that p65 overexpression promoted bladder cancer cell migration by inhibiting RhoGDIα expression. We further demonstrate that the regulatory effect of p65 on RhoGDIα expression is mediated by its upregulation of FBW7, which specifically interacted with RhoGDIα and promoted RhoGDIα ubiquitination and degradation. Mechanistic studies revealed that p65 stabilizing the E3 ligase FBW7 protein was mediated by its attenuating Pten transcription. Taken together, p65 overexpression results in Pten downregulation, and FBW7 protein degradation, and in turn leading to RhoGDIα protein degration and promotings human BC cell migration. The identification of p65/PTEN/FBW7/RhoGDIα axis provides a significant insight into understanding the nature of BC migration.
Note: This abstract was not presented at the meeting.
Citation Format: Yang Li, Junlan Zhu, Jingxia Li, Chuanshu Huang. NFκB p65 overexpression promotes bladder cancer migration via FBW7-mediated degradation of RhoGDIα protein [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 526. doi:10.1158/1538-7445.AM2017-526
Abstract 5265: Breast cancer stem cell inhibition by benzyl isothiocyanate is hampered by induction of Kruppel-like factor 4
Authors: Kim Su-Hyeong , Wan Yong , Singh Shivendra V. 
Published: July 2017

Abstract
Breast cancer is a leading cause of cancer-related deaths among women in the United States. Over the last decade, breast cancer stem cells (bCSC) have been identified and characterized as a key player in breast cancer progression and recurrence. Benzyl isothiocyanate (BITC) is a highly promising cancer chemopreventive constituent of edible cruciferous vegetables such as garden cress. We have shown previously that BITC inhibits bCSC in cultured breast cancer cells (MCF-7 and SUM159 cells) and in spontaneous tumors of mouse mammary tumor virus-neu (MMTV-neu) mice in vivo. Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, is known as both oncogene and tumor suppressor in various types of human cancers and plays an important role in reprogramming differentiated somatic cells into induced pluripotent stem cells. The present study demonstrates that KLF4 impedes bCSC inhibition by BITC. Exposure of breast cancer cells (MCF-7, MDA-MB-231, and SUM159) to pharmacological concentrations of BITC (2.5 and 5 µM) resulted in induction of KLF4 protein, which was accompanied by increase of its transcription. In addition, BITC treatment increased nuclear level of KLF4 in breast cancer cells. KLF4 protein expression was also higher in tumors form BITC-treated MMTV-neu mice compared with the control group. Ectopic expression of KLF4 in MCF-7 cells conferred marked protection against BITC-mediated inhibition of bCSC as evidenced by aldehyde dehydrogenase 1 (ALDH1) activity. Consistent with these observations, BITC-mediated inhibition of bCSC in MCF-7, MDA-MB-231 and SUM159 cells was significantly augmented by RNA interference of KLF4 as evidenced by ALDH1 activity and frequency of mammospheres. KLF4 overexpression also increased cell migration capacity of MCF-7 cells. Furthermore knockdown of KLF4 augmented BITC-mediated inhibition of cell migration in SUM159 cells. These results suggest that anticancer activity of BITC may be enhanced by KLF4 inhibition or knockdown in breast cancer cells. This study was supported by the grant RO1 CA129347-09 awarded by the National Cancer Institute.
Citation Format: Su-Hyeong Kim, Yong Wan, Shivendra V. Singh. Breast cancer stem cell inhibition by benzyl isothiocyanate is hampered by induction of Kruppel-like factor 4 [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 5265. doi:10.1158/1538-7445.AM2017-5265
Abstract 527: Integrated genomic cfDNA/cfRNA profiling for AR-V7 liquid biopsy test in prostate cancer
Authors: Jia Shidong 
Published: July 2017

Abstract
The growth and survival of prostate cancer tumors relies primarily on the functioning of the androgen receptor (AR) signaling pathway. Recent studies suggested that the presence of AR-V7, a c-terminal truncated form of AR, in circulating tumor cells (CTCs) of patients with castration-resistant prostate cancer (CRPC) is associated with inherent and/or acquired resistance to enzalutamide and abiraterone, the stand of care androgen deprivation therapies in prostate cancer. A series of data also indicate that AR-Vs (eg, including AR-V7, ARv567es, AR-T878A, AR-F876L etc) may drive resistance in CRPC. Expression of AR-V7 has been shown to correlate with disease progression and shortened survival. Considering that truncated AR splicing variants with C-terminal loss lack a functional ligand-bingding domain (LBD) and are constitutively active, C-terminal AR-directed therapies may not be effective for patients with AR splicing variants. Circulating tumor cell (CTC)-based AR-V7 tests are currently being tested in the clinic. However, nearly half of the CRPC patients do not have enough CTCs for AR-V7 test, raising the request for a complementary, non-CTC platform to detect AR variants as well as other resistance markers in circulation.
Here we report the development, validation and clinical application of PrediSeq-Prostate, a non-invasive next generation sequencing-based diagnostics platform that offers integrated genomic cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling of prostate cancer, identifying known (such as AR-V7, AR-V9, AR-V2, etc) and novel AR splicing variants, point mutation, copy number, and translocation (such as TMPRSS2-ERG) using a single tube of blood. Using plasma samples from mCRPC patients that developed resistance to enzalutamide and/or abiraterone, PrediSeq-Prostate NGS test identified AR-V7, AR-V2, AR-V3, AR-V4 and other splicing variants that impact diagnosis and therapeutic selection. We also developed a Bio-Rad digital PCR assay measuring AR-V7 and AR-FL (full length) simultaneously. Collectively, PrediSeq NGS and ddPCR assays offer comprehensive genomic profiling of both cfDNA and cfRNA in all patients with prostate cancer, regardless of their status of CTC enumeration. The successful development and clinical validation of these tests has potential to enable precision medicine in prostate cancer.
Citation Format: Shidong Jia. Integrated genomic cfDNA/cfRNA profiling for AR-V7 liquid biopsy test in 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 527. doi:10.1158/1538-7445.AM2017-527