bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2069: A novel berbamine derivative induces apoptosis of chemotherapy-resistant human osteosarcoma cells through activation of ROS/JNK signaling
Authors: Yang Fan , Nam Sangkil , Zhao Robin , Tian Yan , Horne David , Jove Richard 
Published: August 2012

Abstract
Osteosarcoma is the most common primary bone tumor in children and adolescence. There is a critical need to find more potent drugs for patients with metastatic or recurrent disease. Berbamine (BBM) is a natural compound derived from the Berberis amurensis plants. BBM and its derivatives have been shown to have anti-tumor effects in several cancers. Here, we report that a new berbamine derivative, BBMD3 (5 µM), induces apoptosis of human osteosarcoma cells, which are resistant or insensitive to conventional chemotherapy including cisplatin, doxorubicin and methotrexate. BBMD3 inhibited cell viability and induced apoptosis of G292, KHOS and MG-63 human osteosarcoma cells in a time- and dose-dependent manner. BBMD3 activated caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP). Caspase inhibitor (Z-VAD-FMK) could rescue tumor cells from the cytotoxic effects of BBMD3 on cell survival. Importantly, BBMD3 increased phosphorylation of c-Jun N-terminal kinase (JNK) in these tumor cells, resulting in activation of its substrates, c-Jun and c-Fos. Moreover, reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), blocked the phosphorylation of JNK and c-Jun induced by BBMD3. However, Z-VAD-FMK treatment did not inhibit the induction of phosphorylated JNK and c-Jun by BBMD3, suggesting that phosphorylation of JNK and c-Jun occurred before activation of caspases. BBMD3 increased the expression of the pro-apototic gene Bad, associated with apoptosis induction. Finally, BBMD3 also decreased the expression of cyclin D1, a positive cell cycle regulator, which is correlated with growth suppression in osteosarcoma cells. Collectively, these findings indicate that BBMD3 is a potentially promising drug for the treatment of chemotherapy-resistant osteosarcomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2069. doi:1538-7445.AM2012-2069
Abstract 2077: Modulation of reactive oxygen species (ROS) by a dietary agent for the prevention/ treatment of breast cancer
Authors: Arumugam Arunkumar , Boopalan Thiyagarajan , Suman Suman , Das Trinath P. , Damodaran Chendil , Lakshmanaswamy Rajkumar 
Published: August 2012

Abstract
Breast cancer is one of the most common cancers in women, affecting over 1 million women worldwide (208,000 cases in U.S.) and resulting in 400,000 deaths, yearly. The morbidity associated with breast cancer has been only partially impacted by current treatment modalities including surgery, radiotherapy, and adjuvant chemotherapy and/or hormone therapies. There is an immediate need for effective prevention and/or treatment of breast. Changes in reactive oxygen species (ROS) play a pivotal role in these processes. For example, a moderate increase in ROS promotes cell proliferation, but excessive amounts of ROS can induce apoptosis in cancer cells. Therefore, it is possible to manipulate the oxidative stress (redox) system to selectively kill cancer cells. Neem (Azadirachta indica) is a well-known medicinal plant having a wide spectrum of biological activities. In our studies, Ethanolic fraction of Neem Leaf (EFNL) significantly decreased cell viability and induced apoptosis in both estrogen receptor positive (ER+) and triple negative breast cancer (TNBC) cells without causing toxicity to normal primary breast epithelial cells. Oral administration of EFNL (5.0 mg/kg body weight) significantly inhibited the growth of MNU-induced mammary tumors without causing any toxicity. EFNL treatment not only inhibited the growth of established mammary tumors, but also significantly inhibited the growth of any new mammary tumors. These interesting results led us to investigate the mechanism underlying EFNL actions on breast cancer. Our results suggested that EFNL induced Reactive Oxygen Species (ROS) which lead to inhibition of phosphorylation of the pro-survival signal proteins, Akt and its downstream signaling of mTOR and NF kappa B activation. Over expression of antioxidant enzymes such as superoxide dismutases (SOD1 & SOD2) or pharmacological agent [N-acetylcysteine] abrogated EFNL-induced ROS generation, inhibition of cell survival and Akt inactivation in breast cancer cells. These results clearly demonstrate that EFNL induced ROS regulates pro-survival function in breast cancer cells and provides a novel molecular target for breast cancer treatment. The results may provide a preclinical proof-of-principle for a novel targeted therapy for breast cancer cells using EFNL as a nontoxic dietary agent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2077. doi:1538-7445.AM2012-2077
Abstract 2082: The role of cell-cell contacts in the survival of extracellular matrix detached mammary epithelial cells
Authors: Rayavarapu Raju , Schafer Zachary 
Published: August 2012

Abstract
Normal epithelial cells require attachment to the extracellular matrix (ECM) in order to proliferate and survive. Binding to the ECM facilitates the activation of pathways responsible for ATP production and cell survival. When detached from the ECM, normal cells will upregulate apoptotic pathways and will be systematically removed. This detachment-induced apoptosis is known as anoikis. ECM detachment in normal epithelial cells disrupts cellular signaling derived from integrin-mediated basal attachment as well as cadherin assisted signaling from lateral cell contacts. Cadherins, primarily E-cadherin, have been shown to be classic tumor suppressor genes and can prevent the proliferation of cells that fail to assume normal epithelial morphology and cell-cell contacts. The loss of E-cadherin endows an increased invasion capacity to breast tumors and regulation of E-cadherin levels are directly mediated by factors (i.e. Slug) that promote epithelial-to-mesenchymal transition (EMT) and metastasis. Cadherin molecules have previously been reported to interact with other receptor tyrosine kinases, such as EGFR (epithelial growth factor receptor), in order to suppress the ability of the receptor to bind ligand, dimerize and elicit downstream signaling. HER2 is an orphan member of the EGFR family of tyrosine kinases and is a potent oncogene found in 30% of all breast cancer tissue. Previous studies in our laboratory have found a direct correlation between upregulation of survival pathways in ECM detached cells and expression of HER2. In this study, we find that the overexpression of HER2 in non-malignant mammary epithelial cells (MCF-10A) results in substantial aggregation of detached cells, the inhibition of caspase activation and a rescue of ATP production. These data suggest that HER2 plays a role in protecting detached cells from anoikis and this activity may be linked to cell-cell adhesion in suspension. We have found that disruption of cell-cell contacts in HER2-expressing MCF-10A cells utilizing methylcellulose can induce caspase activity and diminish global ATP levels. Preliminary studies also reveal a previously uncharacterized interaction between HER2 and E-cadherin that takes place when E-cadherin dimers are disrupted. Thus, the disruption of E-cadherin dimers in cellular aggregates may facilitate the binding of E-cadherin to HER2 in a fashion that compromises downstream survival signaling. These data together suggest a potential role for E-cadherin as a modulator of HER2 activity and further suggest that the loss of E-cadherin via mechanisms like EMT may function as a means to promote ECM-detached tumor cell survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2082. doi:1538-7445.AM2012-2082
Abstract 2084: Claudin-1 induces resistance to anoikis in Src dependent manner in colon cancer cells
Authors: Sharma Ashok , Singh Amar B. , Smith Joshua J. , Xi Chen , Beauchamp Robert D. , Dhawan Punita 
Published: August 2012

Abstract
Anoikis, a complete loss of cell anchorage triggers apoptosis in primary human colonic epithelial cells (CEC), is often dysfunctional in metastatic cancer cells. We along with other groups have demonstrated that expression of Claudin-1, a tight junction protein, is markedly increased and mislocalized in colon cancer and helps promote the tumor progression especially metastasis. However the underlying mechanism remains poorly understood. To explore, we examined effect of claudin-1 expression upon anoikis. Colon cancer cells genetically manipulated (stable overexpression in SW480 cells and RNA-interference based gene silencing in SW620 cells) for claudin-1 expression were cultured on polyHEMA-coated culture dishes to induce anoikis. Results demonstrated a positive correlation between claudin-1 expression and resistance to anoikis. We also observed a positive correlation between claudin-1 expression, Src (L4A1) and Akt phosphorylation (Ser 473) and Bcl-2 expression in the cells subjected to anoikis. Notably, use of PP2, a Src-kinase inhibitor, inhibited claudin-1-dependent resistance to anoikis (2.5fold) as well as the increases in Akt-phosphorylation and Bcl-2 expression, and thus suggested a causal role of Src-activation in claudin-1-dependent resistance to anoikis. Our further studies revealed that claudin-1 associates with Src in a multi-protein complex that also included ZO-1, a PDZ-domain containing tight junction protein, known to associate with claudin-1and Src. Importantly, claudin-1 contains a PDZ-binding domain in its c-terminal. Deletion of the c-terminal domain of claudin-1 resulted in the loss of the physical association between claudin-1 and Src and a significant loss in claudin-1-dependent resistance to anoikis. Thus, our findings supported a role of claudin-1 in the regulation of colon cancer progression through its association with Src and dependent cell signaling. Our further analysis using a large database of colon cancer patient samples (microarray analysis; 260 colon cancer and 10 adjacent normal colon samples) showed a significant and positive correlation between claudin-1 and Src expression. Taken together, we here report a novel partnering between claudin-1 and Src proteins in colon cancer cells which has a function implication in the regulation of anoikis in a claudin-1/Src/PI3-kinase/Bcl-2-dependent manner. Our findings have clinical significance and have the potential to open potential new therapeutic opportunity in colon cancer treatment and/or management.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2084. doi:1538-7445.AM2012-2084
Abstract 2096: Variants of uncertain clinical significance in cancer predisposition genes: Development of a family studies program for reclassification
Authors: Stuenkel Aaron J. , Lu Ira , Chao Elizabeth C. 
Published: August 2012

Abstract
The identification of genetic variants of uncertain significance is a fairly common, albeit unwelcomed result of gene sequence analyses. The frequency at which these variants are identified will likely continue to increase with the introduction of next-generation sequencing panels and the recent availability of clinical exome sequencing. When applied to testing for cancer predisposition syndromes, accurate variant assessment and classification helps to guide screening, treatment, family planning, and testing of at-risk family members. Multiple resources are available to assess genetic variants: population-based cohort allele frequencies, published literature, in silico prediction tools, gene-specific databases, evolutionary conservation data, and co-segregation studies. Ambry Genetics, a CAP-accredited and CLIA-certified commercial clinical laboratory providing genetic services focused on clinical diagnostics and genomic services, has developed and implemented a complementary family studies program to collect co-segregation data for variants of unknown significance identified through diagnostic testing. The Ambry family studies program is available to all specialties, but is especially active for genes associated with cancer predisposition and intellectual disability. Data collected from the cancer family studies program is combined with published literature, database information, and data compiled with Ambry Variant Analyzer (AVA©), a novel bioinformatics tool, to allow for a comprehensive interpretation of all variants of uncertain clinical significance in cancer predisposition genes. In less than one year, the program has grown to 60 active cancer family studies at the time of submission and a current rate of &gt;5 new applications per week. Variants successfully reclassified due to family studies data include the p.Y327D missense alteration in MEN1 and in-frame deletions in both TP53 and MLH1. Variant reclassification leads to the automatic generation of amended reports for any individual previously identified by our laboratory as a carrier. Immediately distributed to health care professionals, these reports offer the most up-to-date clinical interpretation possible improving medical decision making and clarifying risk of disease. Here we provide an overview of the family studies program and discuss successful variant reclassification via the Ambry model.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2096. doi:1538-7445.AM2012-2096
Abstract 210: Cul4A is an oncogene in malignant pleural mesothelioma
Authors: Ni Jian , Hung Ming-Szu Hung , Mao Jian-Hua , Xu Zhidong , Bravo Dawn T. , Jablons David M. , You Liang 
Published: August 2012

Abstract
Cullin 4A (Cul4A) is important in cell survival, development, growth and the cell cycle, but its role in mesothelioma has not been studied. For the first time, we identified amplification of the Cul4A gene in four of five mesothelioma cell lines. Consistent with increased Cul4A gene copy number, we found that Cul4A protein was overexpressed in mesothelioma cells as well. Cul4A protein was also overexpressed in 64% of primary malignant pleural mesothelioma (MPM) tumours. Furthermore, knockdown of Cul4A with shRNA in mesothelioma cells resulted in up-regulation of p21 and p27 tumour suppressor proteins in a p53-independent manner in H290, H28 and MS-1 mesothelioma cell lines. Knockdown of Cul4A also resulted in G0/G1 cell cycle arrest and decreased colony formation in H290, H28 and MS-1 mesothelioma cell lines. Moreover, G0/G1 cell cycle arrest was partially reversed by siRNA down-regulation of p21 and/or p27 in Cul4A knockdown H290 cell line. In the contrary, overexpression of Cul4A resulted in down-regulation of p21 and p27 proteins and increased colony formation in H28 mesothelioma cell line. Both p21 and p27 showed faster degradation rates in Cul4A overexpressed H28 cell line and slower degradation rates in Cul4A knockdown H28 cell line. Our study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma. Thus, Cul4A may be a potential therapeutic target for malignant pleural mesothelioma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 210. doi:1538-7445.AM2012-210
Abstract 2105: High Galectin-1 expression correlates with poor prognosis and is involved in epithelial ovarian cancer proliferation and invasion
Authors: Lee Jeong-Won , Kim Ha-Jeong , Jeon Hye-Kyung , Cho Young Jae , Park Young Ae , Choi Jung-Joo , Lee Yoo-Young , Choi Chel Hun , Kim Tae-Joong , Bae Duk-Soo , Kim Byoung-Gie 
Published: August 2012

Abstract
Purpose: Galectin-1 (Gal-1) is a 14-kDa laminin-binding galectin involved in several biologic events including regulation of tumor proliferation and metastasis. In this study, we investigated the clinical significance of Gal-1 expression and its functional role in cell proliferation and invasion in epithelial ovarian cancer (EOC). Experimental Design: We evaluated the expression of Gal-1 in 52 serous, 11 endometrioid, and 3 mucinous type EOC tumor samples from 66 patients by immunohistochemistry. In vitro experiments were performed to determine the function of Gal-1 in cell survival, proliferation, and invasion in EOC cells using siRNA and anginex, a Gal-1 inhibitor, as well as recombinant Gal-1 protein. Results: Patients with strong Gal-1 peritumoral staining had poorer progression-free survival (PFS) than patients with weak peritumoral staining (P = 0.03). Inhibition of Gal-1 by siRNA or anginex resulted in the inhibition of cell growth and proliferation of HeyA8 and SKOV3ip1 cells. Moreover, the ability of cells to migrate was significantly reduced by treatment of cells with Gal-1 siRNA but was increased by treatment of cells with recombinant Gal-1. When we evaluated the interaction between fibroblasts (H HESC) and cancer cells (A2780-CP20), we found that MMP-2 expression in cancer cells was affected by Gal-1 secreted by fibroblast cells, which suggests that Gal-1 in human fibroblasts might affect the invasive abilities of tumor cells. Conclusion: Our results suggest that Gal-1 expression is a potential prognostic factor for PFS and that Gal-1 could be a novel treatment target in EOC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2105. doi:1538-7445.AM2012-2105
Abstract 2118: Particulate chromate induces persistent DNA double strand breaks resulting in disruption of homologous recombination repair in human lung cells
Authors: Qin Qin , Xie Hong , Holmes Amie L. , Wise Sandy S. , Wise John P. 
Published: August 2012

Abstract
Hexavalent chromium (VI) is a well-documented respiratory toxicant and carcinogen. The most carcinogenic form is the particulates, which produce numerous types of DNA damage including DNA double strand breaks. The aim of this study is to determine the genotoxicity of particulate chromate and investigate cellular responses of repair proteins after chronic exposure. We used zinc chromate as a representative hexavalent chromium compound because it has been shown to be carcinogenic and induce tumors in epidemiology studies and experimental animals. We investigated the DNA double strand break formation using both comet assay and immunofluorescence staining. We exposed cells to zinc chromate for 24, 48, 72 96 and 120 hours and found it induced concentration-dependent increases in DNA double strand breaks by both measures. We further investigated the kinetics of repair protein after chronic zinc chromate exposure. We developed human lung cells expressing green fluorescent protein-tagged 53BP1 (GFP-53BP1) and generated time-lapse videos of chromate treated cells. We observed residual focal formation of 53BP1 after chronic zinc chromate exposure, which indicate some DNA double strand breaks persist. There are two repair pathways that can be utilized to repair DNA double strand breaks. Non-homologous end joining (NHEJ) is active throughout the cell cycle while homologous recombination (HR) is active in late S and G2 phases. We first investigated the sub-cellular distribution of HR proteins including MRE11, phophorylated ATM and Rad51. We found that the nuclear fraction of HR repair proteins increased in 24 hours indicating HR is active. However, it largely decreased over time. We also observed concentration- and time-dependent decrease in Rad51 foci formation, which strongly suggest that HR is inhibited. Future work will focus on elucidating NHEJ repair pathway and identifying key proteins involved in transitions between two repair pathways. This work was supported by NIEHS grant ES016893 (J.P.W.), cooperative agreement #EP-08-01 through the Maine Space Grant Consortium (J.P.W.) and the Maine Center for Toxicology and Environmental Health at the University of Southern Maine.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2118. doi:1538-7445.AM2012-2118
Abstract 213: RNF126 E3 ubiquitin ligase targets p21cip for ubiquitin-mediated degradation
Authors: Zhi Xu , Zhao Dong , Zhou Zhongmei , Chen Ceshi 
Published: August 2012

Abstract
Many E3 ubiquitin ligases, such as Mdm2 and Skp2, are potential therapeutic targets for cancers. To identify novel oncogenic E3 ubiquitin ligases as anti-cancer targets, we screened an E3 ubiquitin ligase siRNA library containing siRNA pools against 555 individual E3s using the SRB assay in the MDA-MB-231 breast cancer cell line and the PC3 prostate cancer cell line. RNF126 was identified and validated as a promising candidate from this screening. Depletion of RNF126 dramatically decreased cell viability in these cancer cell lines. Consistently, RNF126 depletion delayed cell cycle G1/S progression and decreased cell proliferation. By a protein array analysis, we found that RNF126 depletion increased the cell cycle dependent kinase inhibitor p21cip protein levels in both MDA-MB-231 and PC3. Knockdown of RNF126 stabilized the p21 protein rather than increased the p21 mRNA levels. We demonstrated that RNF126 interacts with p21 in cells and in vitro, and the protein-protein interaction depended on the N-terminal and middle parts of RNF126. RNF126 over-expression increased the p21 protein ubiquitination in an E3 ligase activity dependent manner. RNF126 knockdown induced loss of cell viability in MDA-MB-231 and PC-3 can be partially rescued by depletion of p21. RNF126 stable knockdown in SW527 inhibited tumor growth in SCID mice. Finally, we found that RNF126 is highly expressed in ER negative breast cancer cell lines and negatively correlated with the p21 expression levels. These findings suggest that RNF126 promotes cancer cell proliferation through targeting p21 for ubiquitin-mediated degradation. RNF126 could be a novel therapeutic target in breast and prostate cancers. This study was partially supported by a grant from the American Cancer Society (RSG-08-199-01), grants from National Nature Science Foundation of China (81072162, 81120108019, and U1132605), and a grant from Yunnan Province High-Profile Talents Program (2010CI114).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 213. doi:1538-7445.AM2012-213