bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4033: Identification and characterization of a truncated RUNX3 gene variant with putative dominant-negative function
Authors: Lau Wen Min , Chong Hui Shan , Lopez Kirsten Anne Pagaduan , Teng Eileen , Chan Shing Leng 
Published: June 2012

Abstract
Stem cells and cancer stem cells show a distinct proliferative potential for forming clonal floating colonies in vitro, termed tumor spheres. We have generated tumor spheres from a clinical gastric cancer sample (GCIC38) using serum-free culture, and expression of EpCAM and cytokeratin proteins confirmed the epithelial origin of these cells. GCIC38 sphere-derived cells were able to initiate tumors in NOD/SCID mice that recapitulate the tumor in the gastric cancer patient. Real-time PCR analysis showed that in contrast to human gastric cancer cell lines AGS, SNU16 and NCI-N87, GCIC38 sphere-derived cells express relatively high levels of stem cell markers such as SOX2, Musashi-1, and Bmi-1. Surprisingly, mRNA expression of the well-known tumor suppressor for gastric cancer, RUNX3, was found to be 4.6 and 16-fold higher than that of SNU16 and NCI-N87 cells respectively. Consistently, western blot analyses showed that GCIC38 sphere-derived cells express high levels of RUNX3 compared to a panel of gastric cancer cell lines. Immunofluorescence staining confirmed that RUNX3 was expressed in the nuclei of these cells, ruling out the possibility of RUNX3 protein mislocalization. To further characterize RUNX3 in GCIC38 sphere-derived gastric cancer cells, we cloned and identified a novel truncated 0.4kb RUNX3 variant (RUNX3-LG) that is expressed concurrently with the 1.2kb full length RUNX3 transcript (wt-RUNX3) in these cells. Sequence analysis revealed that RUNX3-LG is a truncated form of RUNX3 variant 2 encoded by a transcript utilizing the P2 promoter. There are no mutations in the wt-RUNX3 transcript whilst exons 3, 4 and 5 are spliced out in the RUNX3-LG transcript resulting in the deletion of RUNT domain in the RUNX3-LG protein. Immunoprecipitation studies using RUNX3 antibodies showed endogenous expression of a 15kDa protein in GCIC38 sphere-derived cells, concordant with the predicted size of RUNX3-LG protein. Preliminary data show that ectopic over-expression of RUNX3-LG in AGS gastric cancer cells results in reduced expression of RUNX3 target genes Claudin-1, S100A2 and p21. We propose that RUNX3-LG may be a dominant negative variant in gastric cancer cells with high wt-RUNX3 expression, which may abrogate wt-RUNX3 gene function including its tumor-suppressive effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4033. doi:10.1158/1538-7445.AM2011-4033
Abstract 4036: Chromosomal amplification of LRRK2 is required for oncogenic MET signaling in papillary renal and thyroid carcinomas
Authors: Looyenga Brendan D. , Furge Kyle A. , Dykema Karl J. , Koeman Julie , Swiatek Pamela J. , Giordano Thomas J. , West Andrew B. , Resau James H. , Teh Bin T. , MacKeigan Jeffrey P. 
Published: June 2012

Abstract
The receptor tyrosine kinase MET is frequently amplified in human tumors, resulting in high cell surface densities and constitutive activation even in the absence of growth factor stimulation by its endogenous ligand, HGF. We sought to identify mechanisms of signaling crosstalk that promote MET activation by searching for kinases that are coordinately dysregulated with wild-type MET in human tumors. Bioinformatic analysis identified leucine-rich repeat kinase-2 (LRRK2), which is amplified and overexpressed in papillary renal and thyroid carcinomas. Downregulation of LRRK2 in cultured tumor cells compromises MET activation and selectively impairs MET signaling to mTOR and STAT3. Loss of these critical mitogenic pathways induces cell cycle arrest and cell death concomitant with loss of ATP production and induction of autophagy. Interestingly, knockdown of LRRK2 precisely phenocopies treatment of tumor cells with the endocytic inhibitor chlorpromazine, suggesting that LRRK2 is required for efficient internalization or post-endocytic trafficking of activated MET receptors. We propose that coordinate amplification of LRRK2 and MET functions to promote endosomal signal transduction by MET, which is required for transformation in papillary renal and thyroid cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4036. doi:10.1158/1538-7445.AM2011-4036
Abstract 4038: Aspirin acetylates p53 in colon cancer cells and induces the expression of p21 and Bax: Identification of aspirin acetylated sites on rp53
Authors: Chivukula Raghavender , Marimuthu Srinivasan , Alfonso Lloyd , Hagen Fred , Gunaje Jayarama B. 
Published: June 2012

Abstract
Several studies over the past decade have shown that regular use of aspirin reduces the risk of cancers of various organs such as colon, breast, lung and prostate tissue. The mechanism by which aspirin exerts its anti-cancer effects is not clearly understood. Previous studies from our laboratory showed that aspirin acetylates the tumor suppressor protein p53 and modulates target gene expression in MDA-MB-231 breast cancer cells. We now have extended these studies to include HCT116 (wt-type p53) and HT-29 (mutant p53) colon cancer cells. Using anti-acetyl p53 antibody, we show in the present study that aspirin acetylated p53 at lysine 382 in both cell types. It also detected two other proteins of size 63 kDA and 35 kDa, which are likely to represent other isoforms of p53. Aspirin also acetylated recombinant p53 (rp53) in vitro, suggesting that the mechanism of cellular acetylation may be through a direct non-enzymatic chemical reaction. Mass spectrometry analysis of the aspirin-treated rp53 identified 7 acetylate lysine residues. In HCT116 and HT-29 cells, aspirin-induced acetylation of p53 was observed in a concentration dependent manner. The acetylated p53 was localized to the nucleus. Consistent with these observations, aspirin transiently increased p21, a protein involved in cell cycle arrest; however, the expression of the proapoptotic protein, Bax, was sustained. Treatment of cells with the anti-cancer drug, camptothecin, induced sustained induction of p21. Co-treatment with both camptothecin and aspirin decreased the expression of p21. Aspirin also potentiated camptothecin-induced cell death as measured by MTT assay, clonogenic cell survival assay and annexin V binding assay. Our results suggest that p53 pathway may contribute to the anti-cancer properties of aspirin.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4038. doi:10.1158/1538-7445.AM2011-4038
Abstract 4042: Activation of ErbB2 results in decreased Par6-associated aPKC kinase activity
Authors: Krishnamurthy Kannan , Aranda Victoria , Muthuswamy Senthil 
Published: June 2012

Abstract
Loss of epithelial cell polarity is often associated with the development of carcinoma. Polarized MDCK cells and MCF-10A mammary epithelial cells grown in 3D are useful model systems to study the regulation of cell polarity in vitro and to investigate the interaction of oncogenes and cell polarity proteins. Using these experimental models, we have previously demonstrated that activation of the oncogene ErbB2 disrupts apical-basal polarity in mammary epithelial cells. Activated ErbB2 associates with the Par6-aPKC polarity complex and the interaction between Par6 and aPKC is indispensible for ErbB2-mediated disruption of cell polarity and inhibition of apoptosis. Following ErbB2 activation, we find a decrease in Par6-associated aPKC kinase activity. Furthermore, kinase dead aPKC cooperates with activated ErbB2 to transform mammary epithelial cells in vitro, without inducing any changes in proliferation of cells grown on plastic dishes. Taken together, our data implicate a target (or targets) of aPKC as a likely determinant of ErbB2-mediated disruption of cell polarity and transformation. Identification of these substrates could lead to the development of novel biomarkers to monitor the progression of ErbB2 positive tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4042. doi:10.1158/1538-7445.AM2011-4042
Abstract 4242: Clinically used nitrocatechols and EGCG synergistically inhibit lung cancer cells in vitro
Authors: Forester Sarah C. , Lambert Joshua D. 
Published: June 2012

Abstract
Polyphenols are likely to be responsible for the anticancer effects of green tea, with (−)-epigallocatechin-3-gallate (EGCG) the most well-studied. EGCG reduces lung cancer cell viability effectively in vitro, yet it is methylated by catechol-O-methyl transferase (COMT), limiting its effectiveness in inhibiting cancer cell growth. The nitrocatechol drugs entacapone and tolcapone are potent inhibitors of COMT and are used to mitigate effects of Parkinson's disease. Here, we investigated the synergistic effects of entacapone/tolcapone and EGCG in human (H1299) and murine (CL-13) cell lines. The IC50s of entacapone, tolcapone, and EGCG were 76.8, 29.3, and 174.9 μM, respectively in H1299 cells, and 50.7, 19.7, and 181.5 μM, respectively in CL-13 cells following treatment for 72 h. The IC50s were dramatically reduced when entacapone and tolcapone were used in combination with EGCG. The interactions were determined to be synergistic using isobolographic analysis. Inhibition of COMT-mediated methylation of EGCG by entacapone and tolcapone was also measured by LC-MS over 30 min and the IC50 values were 10 and 20 μM, respectively. The anticancer effects of the nitrocatechols and EGCG were also evaluated in pathways of apoptosis (TUNEL) and cell cycle (flow cytometry). In conclusion, the combination of EGCG and entacapone or tolcapone has greater lung cancer growth inhibitory activity than treatment with any of the single compounds. The mechanistic basis for this synergy is likely due in part to COMT inhibition, yet other mechanisms are also likely to play a role. Funded by NIH grant AT004678.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4242. doi:10.1158/1538-7445.AM2011-4242
Abstract 4243: Potential protective role of phytoalexins derived from soybean by biotic elicitor on inflammatory mechanism
Authors: Kim Hyo Jung , Jung Chae Lim , Nam Dae Hwan , Lim Ji Sun , Han Min Young , Hong Ye-Seul , Kim Jong-Sang 
Published: June 2012

Abstract
Given the preventive effect of soy intake against several chronic diseases, this study was conducted to investigate the inhibitory activity of phytoalexins glyceollins derived from soybean isoflavones by treating with biotic elicitor against LPS-induced inflammation in RAW 264.7 cell culture system. Our data showed that glyceollins effectively inhibited NO production, IL-6 release, and COX-2 expression induced by LPS. In particular, glyceollins suppressed the LPS-induced phosphorylation of NF-B p65, suggesting that the compounds inhibit the production of NO and transcriptional activation of COX-2 by regulating NF-B activity. In another experiment we found that glyceollins enhanced the expression of heme oxygenase 1 and repressed the phosphorylation of ERK1/2 and p38 but not JNK in LPS-treated RAW 264.7 cells. Glyceollins also reduced TPA-induced skin inflammation in mouse model, confirming the anti-inflammatory activity of glyceollins in vivo system as well as cell culture system. Taken together, glyceollins merit further study as potential therapeutic agents for inflammatory disorders.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4243. doi:10.1158/1538-7445.AM2011-4243
Abstract 4245: Preclinical study of puquitinib, a novel orally available PI3K inhibitor in phase I clinical trials
Authors: Xie Chengying , Xu Yongping , Lou Liguang 
Published: June 2012

Abstract
Extensive evidence implicates activation of PI3K pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. In this report, we detailed the pharmacologic properties of puquitinib, a novel orally available PI3K inhibitor structurally distinct from all those known so far. Puquitinib reduced the levels of phosphatidylinositol-3,4,5-trisphosphate (PIP3), a product of PI3K, and inhibited the phosphorylation, translocation and membrane ruffling of AKT, the signaling component downstream from PI3K. The inhibitory effects of puquitinib on PI3K signaling were correlated with its potent anti-proliferative activity in a panel of tumor cells. Puquitinib also demonstrated potent anti-angiogenic effects in the tubule formation and cell migration assays of human umbilical vein endothelial cells, and micro-vessel spouting from matrigel-embedded rat aortic rings. Oral administration of puquitinib showed strong antitumor activity in various human cancer xenograft models without any noticeable toxicity, along with the reduction of phosphorylated AKT in tumor tissues. Collectively, the preclinical data show that puquitinib is a potent PI3K inhibitor with favorable pharmaceutical properties. Puquitinib is currently being evaluated in phase I clinical trials in China.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4245. doi:10.1158/1538-7445.AM2011-4245
Abstract 4326: Responses of a direct in vivo xenograft model of melanoma to MKK1/2 inhibitor
Authors: Sethuraman Jyothi , Luo Yuchun , Sung Hyojin , Fujita Mayumi , Ahn Natalie G. 
Published: June 2012

Abstract
Metastatic melanoma is the most aggressive form of skin cancer, accounting for 80% of skin cancer deaths due to its high resistance to conventional chemotherapy. Recent studies have shown that metastatic melanomas are susceptible to targeted therapeutics using inhibitors of BRAF or MKK1/2 protein kinases. Here, we study the effect of the MKK1/2 inhibitor, AZD6244, on a direct in vivo xenograft model of melanoma, as well as the effect of MKK1/2 inhibitors, AZD6244 and CI1040 and the BRAF-V600E inhibitor, PLX4720, on established cell lines and cells from direct in vivo xenografts grown in 2D culture. Treatment with CI1040 elicited strong cell death responses in six of nine established melanoma cell lines, reaching 65-80% apoptosis after 48 h. Xenografts of established melanoma cell lines were also responsive to MKK1/2 inhibitor, showing suppressed tumor growth in animals treated with CI1040 in the presence or absence of temozolomide. Likewise, MKK1/2 inhibitor suppressed tumor growth in a direct in vivo xenograft model of melanoma, where tumors harboring BRAF-V600E mutations showed complete growth inhibition in response to AZD6244. One tumor harboring BRAF-WT showed partial growth suppression with AZD6244 alone, but complete suppression was achieved when AZD6244 was combined with temozolomide. Unexpectedly, cells derived from direct in vivo xenografts and grown in 2D culture showed relatively low apoptotic responses when treated with MKK1/2 or BRAF inhibitors. The results suggest that tumor and cell growth conditions might influence mechanisms underlying the oncogene addiction response to constitutive activation of the BRAF/MKK/ERK pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4326. doi:10.1158/1538-7445.AM2011-4326
Abstract 4337: Interactions of brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) systems in neuroblastoma: New insight into mechanisms of BDNF's pro-survival effects
Authors: Czarnecka Magdalena K. , Kuan-Celarier Anna , Lu Congyi , Everhart Lindsay , Kitlinska Joanna 
Published: June 2012

Abstract
BDNF is a known survival factor for neuroblastomas (NB) and is implicated in the development of their chemoresistance. NPY, on the other hand, is a sympathetic neurotransmitter, which is highly released from NB tumors. The elevated NPY levels in NB patients are associated with poor clinical outcome, which is in agreement with its Y2 receptor (Y2R)-mediated proliferative effects on NB cells and pro-angiogenic activities. In normal sympathetic neurons, BDNF has been shown to up-regulate NPY expression, while NPY itself has been implicated in promoting their survival. Therefore, we sought to determine if similar interactions between BDNF and NPY systems occur in NB cells.
We have found that BDNF up-regulates expression of both NPY and its Y2Rs in native NB cells, as well as SH-SY5Y cells transfected with BDNF receptor – TrkB (SH-SY5Y/TrkB). However, even more dramatically, BDNF induces expression of another NPY receptor – Y5R, which is not detectable in most NB cell lines under basal conditions. In agreement with this, expression of Y5Rs correlated with TrkB and BDNF expression in human NB samples. In addition, Y5R seems to be directly involved in BDNF signaling. In SH-SY5Y/TrkB cells, BDNF-induced activation of p44/42 MAPK is significantly reduced by selective Y5R antagonist, CGP 71683, but not by Y2R antagonist, BIIE 0246. Interestingly, the Y5R antagonist had no effect on Akt activation stimulated by BDNF. Thus, these data suggest specific cross-talk between TrkB and Y5R signaling leading to activation of p44/42 MAPK pathway.
Since BDNF is a known survival factor for NB cells, we sought to determine if pro-survival activity of BDNF is mediated by NPY. Chemotherapy was found to up-regulate the expression of both BDNF and NPY systems. This was further supported by elevated expression of NPY and its Y5Rs in cells derived from a chemotherapy-treated patient (CHLA-20, SMS-KANR) as compared to cells derived from primary tumors of the same patient (CHLA-15, SMS-KAN). In the functional studies, NPY mimicked the anti-apoptotic effect of BDNF in chemotherapy-treated NB cells. Moreover, as observed with MAPK activation, blocking Y5Rs, but not Y2Rs, reduced the pro-survival activity of BDNF in these cells.
In summary, while Y2R is the main NPY R constitutively expressed in NBs and responsible for its proliferative effect, expression of Y5R is induced by BDNF and chemotherapy, subsequently enhancing the pro-survival functions of NPY. These anti-apoptotic actions of NPY can additionally augment the known direct survival effects of BDNF.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4337. doi:10.1158/1538-7445.AM2011-4337
Abstract 4369: Eradication of chemotherapy-resistant CD44+ human ovarian cancer stem cells in C.B-17/SCID mice by intraperitoneal administration of Clostridium Perfringens Enterotoxin (CPE)
Authors: Santin Alessandro D. , Cocco Emiliano , Bellone Stefania , Casagrande Francesca , Bellone Marta , Todeschini Paola , Varughese Joyce , Silasi Dan-Arin , Azodi Masoud , Rutherford Thomas , Schwartz Peter , Pecorelli Sergio 
Published: June 2012

Abstract
Emerging evidence has suggested that the capability to sustain tumor formation, growth and resistance to chemotherapy in ovarian as well as other human malignancies, exclusively resides in a small proportion of tumor cells termed cancer stem cells (CSC). If this hypothesis is correct, different therapeutic approaches need to be considered for the elimination of the cancer stem cell population. During the characterization of CD44+ ovarian CSC we found a high expression of the genes encoding for claudin-4. Because this tight junction protein is the natural high affinity receptor for the cytotoxic effect of Clostridium Perfringens Enterotoxin (CPE), we have extensively investigated the sensitivity of ovarian CSC to CPE treatment in vitro and in vivo. We report that CD44+ ovarian CSC expressed claudin-4 gene at significantly higher levels when compared to matched autologous CD44- ovarian cancer cells and, regardless of their higher resistance to chemotherapeutic agents, died within 1 hr to the exposure to 1.0 μg/mL of CPE in vitro. Importantly, multiple intraperitoneal (i.p.) administration of sublethal doses of CPE in SCID mouse harboring established xenografts of chemotherapy resistant CD44+ ovarian CSC had a significant inhibitory effect on tumor progression leading to the cure and/or long term survival of all treated animals (p = 0.001). CPE may represent an unconventional, potentially highly effective strategy to eradicate chemotherapy resistant CSC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4369. doi:10.1158/1538-7445.AM2011-4369
Abstract 437: Longitudinal imaging of the pancreatic cancer tumor microenvironment
Authors: Momiyama Masashi , Suetsugu Atsushi , Tome Yasunori , Bouvet Michael , Chishima Takashi , Endo Itaru , Hoffman Robert M. 
Published: June 2012

Abstract
In order to visualize the tumor microenvironment (TME) in pancreatic cancer, the MIA PaCa-2 human pancreatic cancer cell line, expressing red fluorescent protein (RFP), was orthotopically transplanted in nude mice or transgenic mice expressing nestin-GFP. In the nestin-GFP mouse, nascent blood vessels which vascularize the growing tumor are labeled with GFP. A peritoneal flap was made on the left flank of nude mice. The tail of the pancreas was fixed on the peritoneal flap in order to image tumors on the pancreas directly and repeatedly. Color-coded imaging was observed with the Olympus OV100 Small Animal Imaging System under high magnification. The growing tumor expressing RFP, nascent blood vessels expressing GFP, and the interaction between RFP cancer cells and GFP macrophages were observed in real time. Imaging could be carried out until the tumor exceeded the size of the flap which occurred at approximately 21 days after tumor implantation. This mouse model for imaging in the pancreas TME will enable a deeper understanding of tumor-host interaction pancreatic cancer and make it possible to study new therapeutics for pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 437. doi:10.1158/1538-7445.AM2011-437