bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4144: The treatment with a derivative of Vitamin A (ATRA) modulates the expression and subcellular localization of Protein Kinase C (PKC) delta and induces growth inhibition in normal and tumor derived mammary cells
Authors: Berardi Damian E. , Bessone María I. Díaz , de Kier Joffé Elisa D. Bal , Todaro Laura B. , Urtreger Alejandro J. 
Published: February 2011

Abstract
Retinoids may exert some of their effects on cell differentiation and malignant phenotype reversion through the interaction with different PKC isoforms. In the present work we addressed the following issues: A)- the role of ATRA on the in vitro growth potential of LM3, a murine mammary tumor-derived cell line; NMuMG, a normal murine mammary cell line and MDA-MB231, a human breast cancer-derived cell line. B)- the effect of retinoid treatment on the expression and subcellular distribution of PKCδ and C)- the importance of PKCδ in the activity of retinoid receptors.
ATRA treatment (1μM, 72h) induced a significant growth inhibition in the analyzed murine cell lines. This phenomenon was associated with the reduction of pERK1 levels (80±9% and 40±5% in LM3 and NMuMG cells respectively) and the increase of the cell cycle inhibitor p27 in the nuclear fraction without altering the expression of Cyclin D1 in both murine cell lines. None of these modulations were observed in the ATRA unresponsive MDA-MB241 cell line.
By Western blot we could determine that 72h treatment with ATRA induced an increase of PKCδ protein levels both in the nuclear fraction of LM3 cells (4-fold) and in the cytoplasm (2- and 3-fold for LM3 and NMuMG cells respectively). On the contrary, in MDA-MB241 cells PKCδ expression was reduced after ATRA exposure.
Interestingly, pharmacological silencing of PKCδ in LM3 cells prevented the activation of retinoid receptors by ATRA, as evidenced by a reporter gene assay (RARE-Luciferase).
Our results suggest that, in ATRA-responsive cells, the treatment with this vitamin A derivate inhibits in vitro growth, by reducing mitogenic signaling, by increasing the expression of a cell-cycle inhibitory protein as well as by increasing PKCδ an isoform usually associated with growth inhibition and apoptosis induction. The subcellular localization was also altered by this treatment in LM3 cells. Moreover, the effect of ATRA exerted through the activation of its specific nuclear receptors would depend on the nuclear translocation of this PKC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4144.
Abstract 4148: Rapamycin potentiates the effects of paclitaxel in uterine papillary serous carcinoma (UPSC) cells through inhibition of cell proliferation and induction of apoptosis
Authors: Mendivil Albert , Zhou Chunxiao , Cantrell Leigh , Gehrig Paola , Malloy Kim , Bae-Jump Victoria L. 
Published: February 2011

Abstract
Objectives: Treatment of women with uterine papillary serous carcinoma (UPSC) using cytotoxic chemotherapeutic agents has been met with limited success. This has led to the search for an additional agent that could be used in combination with more traditional therapies to dramatically increase therapeutic efficacy while not increasing toxicities. Among the most promising of these for endometrial cancer are inhibitors of the mammalian target of rapamycin (mTOR). Rapamycin and paclitaxel have been found to be synergistic in type I endometrial cancer cell lines. Thus, our objective was to examine the effects of combined therapy with rapamycin and paclitaxel in a UPSC cell line.
Methods: The UPSC cell line, SPEC-2 was used. Cell proliferation was assessed after exposure to rapamycin or paclitaxel alone or in combination, and viable cell densities were determined by measuring conversion of the metabolic dye, MTT. Apoptosis was assessed by flow cytometric analysis of annexin-V expression. hTERT expression, as a marker of telomerase activity, was determined by real-time RT-PCR. Western immunoblotting was performed to determine the expression of the downstream targets of the mTOR pathway, including phosphorylated S6 and 4E-BP-1.
Results: Paclitaxel inhibited proliferation in a dose-dependent manner in the SPEC-2 cell line, with an IC50 value of 1-10 nM. Simultaneous exposure of cells to various doses of paclitaxel in combination with rapamycin (1 nM) resulted in a significant synergistic anti-proliferative effect (p=0.0032-0.0059). In addition, rapamycin increased paclitaxel-induced apoptosis over that of paclitaxel alone. Rapamycin decreased hTERT mRNA expression while paclitaxel alone had no effect on telomerase activity. Rapamycin decreased phosphorylation of the S6 and 4E-BP-1 proteins after 24 hrs of exposure. In contrast, paclitaxel had little effect on 4E-BP-1 phosphorylation but did induce phosphorylation of S6 at higher doses (10 nM). Treatment with paclitaxel and rapamycin resulted in overall decreased phosphorylation of both S6 and 4E-BP-1.
Conclusions: We demonstrate that rapamycin potentiates the effects of paclitaxel in UPSC cells through inhibition of cell proliferation and induction of apoptosis. This suggests that the combination of rapamycin and paclitaxel may be a promising effective targeted therapy for UPSC, an aggressive and often lethal subtype of endometrial cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4148.
Abstract 4149: A newly developed GSK-3 inhibitor, CG9, inhibits breast cancer cell proliferation through estrogen receptor α degradation
Authors: Kim Hyun Mi , Kim Choung-Soo , Lee Je-Hwan , Cho Joong Myung , Hwang Jung Jin , Jang Sejin , Ro Seonggu , Hyun Young-Lan , Choi Jene 
Published: February 2011

Abstract
GSK-3 (glycogen synthase kinase-3) has a major role in Wnt and Hedgehog signaling pathways and regulates the cell cycle, stem cell renewal and differentiation, apoptosis, and insulin action. The pharmacological inhibitors of GSK-3 could be used to treat several diseases, including Alzheimer's disease, other neurodegenerative diseases and diabetes. In this study, we investigated the cellular and molecular effects of a newly developed GSK-3 inhibitor, CG9, in seven breast cancer cell lines of the NCI-60 cell line panel. CG9 treatment increased inhibitory phosphorylation of GSK-3α/β (Ser21/9), whereas decreased activating phosphorylation of GSK-3β (Tyr216), together with the overall reduction of the level of GSK-3 proteins. CG9 also induced growth inhibition and stimulated a caspase-dependent apoptotic pathway regardless of estrogen receptor (ER) positivity with IC50 of 12 μM in T47D to ≤ 0.1 μM in MCF7 cells. The GSK inhibitor down-regulated the cellular levels of ERα and cyclin D in ERα-positive MCF7 cells. Immunoprecipitation experiments showed that CG9 treatment inhibits the interaction of Hsp90 with ERα in cytoplasm. Taken together these results indicate that CG9 may be an effective anti-cancer agent in human breast cancers. Currently, we are investigating the efficiency of CG9 compared with that of antiestrogen tamoxifen (Tam) and a possibility of combined treatment with CG9 and Tam.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4149.
Abstract 4153: Short term opioid receptor blockade inhibits cancer cell proliferation independent of immune function by upregulation of the OGF-OGFr axis: A tissue culture model of low dose naltrexone (LDN)
Authors: Donahue Renee N. , McLaughlin Patricia J. , Zagon Ian S. 
Published: February 2011

Abstract
The opioid growth factor (OGF) is an autocrine produced and constitutively expressed peptide that interacts with the OGF receptor (OGFr) and subsequently targets the cyclin dependent kinase inhibitory (CKI) pathways to inhibit proliferation at the G1/S phase of the cell cycle. Naltrexone (NTX) is a nonselective opioid receptor antagonist that blocks this interaction. In vivo administration of a low dosage of NTX (LDN, 0.1 mg/kg) blocks opioid receptors for 4-6 h, resulting in a compensatory upregulation of OGF and OGFr. Following clearance of NTX, the elevated levels of OGF and OGFr interact to decrease cell proliferation. To investigate whether LDN inhibits cancer cell proliferation independent of immune function, a tissue culture model using short term NTX in human ovarian cancer cell lines (SKOV-3, OVCAR-3) was established. Cell replication and cell number were determined over 96 h in cultures treated with a single 6 h application of NTX (10−6 M). In SKOV-3 and OVCAR-3 cultures, cell number was decreased by 21-28% and 27-32%, respectively, between 48 and 96 h; DNA synthesis was inhibited ∼ 33% at 72 h. Peptide specificity studies using a variety of classical μ, δ, or κ opioid receptor agonists confirmed that only OGF inhibited cell number. Antibody neutralization of OGF in cultures revealed that endogenous OGF invoked the inhibitory growth effects of short term NTX. To evaluate which opioid receptor mediated the inhibitory action of short term NTX on growth, cultures were treated with siRNAs against the μ, δ, κ, and OGFr receptors; only OGFr was associated with short term NTX treatment. Immunocytochemical studies and semiquantitative analyses documented an upregulation of OGF and OGFr expression following short term NTX exposure in cancer cells; western blot analysis and receptor binding for OGFr revealed 2-fold increases of receptors 48 h after a brief exposure to NTX. NTX's inhibitory action was not related to apoptosis (TUNEL) or necrosis (trypan blue staining). To investigate whether short term NTX's action on cell proliferation was transduced by the p16 and/or p21 CKI pathways, siRNAs for p16 and p21 were utilized in combination with short term NTX. Silencing of p16 and/or p21 blocked the inhibitory action of short term NTX, indicating a mechanism directed toward the CKI pathways. Independent of immune function, short term opioid receptor antagonism has been demonstrated to inhibit cancer cell proliferation by upregulation of the OGF-OGFr axis. Upregulation of the OGF-OGFr axis by a brief opioid receptor blockade may provide a novel target for biotherapy of cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4153.
Abstract 4162: Gal4/UAS-mediated pancreatic tumorigenesis in zebrafish
Authors: Liu Shu , Parsons Michael J. , Davison Jon M. , Leach Steven D. 
Published: February 2011

Abstract
Pancreatic cancer remains the 4th deadliest cancer in the United States in 2009. The 5-year survival rate for all stages remains at 5%, the lowest rate among major malignancies. Lack of methods for early detection, as well as ineffective treatments, contribute to the poor outcome of the disease. Over 90% of the pancreatic cancers are pancreatic ductal adenocarcinomas (PDACs). Mutations in the KRAS gene were found in majority of the PDAC lesions and played critical role in the initiation of tumorigenesis as demonstrated in transgenic mouse models. Recent pancreatic cancer genome sequencing results have highlighted the major pathways that can be altered in PDACs. The study also produced a list of novel oncogene candidates that may play parts in the rise of pancreatic cancer. To facilitate the evaluation of these candidate oncogenes’ function in pancreatic cancer in vivo, we developed zebrafish models that can overexpress transgenes specifically in pancreas, alone or in the presence of a human KRAS mutant transgene. The transgenes were introduced into zebrafish via Tol2 transposon elements. The Gal4/UAS transcriptional regulatory system was utilized to ensure targeted expressions of multiple transgenes in the pancreas, controlled by the regulatory element of the Ptf1a gene, a transcription factor critical for pancreas development. Pancreas-specific expression of the mutant KRAS transgene alone in zebrafish can give rise to pancreatic cancers similar to those observed in humans. We now have the opportunity to functionally assess a wide variety of genetic lesions for their ability to modify pancreatic cancer initiation and/or progression, achieving a level of throughput not technically feasible in the mouse.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4162.
Abstract 4163: JNK2 reduction increases intestinal tumor susceptibility in Apc+/− mice
Authors: Bi Xiuli , Hu Dong , Pohl Nicole M. , Yin Zhinan , Yang Wancai 
Published: February 2011

Abstract
Previous studies have shown distinct functions between c-jun NH2 terminal kinases (JNK) 1 and 2. Indeed, loss of JNK1 causes spontaneous intestinal tumor formation in mice (Tong et al, Am. J. Pathol, 2007; Hu et al, Carcinogenesis, 2008), but loss of JNK2 does not have any phenotype in intestine, although in vitro studies have shown that JNK2, like JNK1, interacts with and inhibits β-catenin signaling, in which GSK3β and proteasome pathway play a critical role (Hu et al, LoS One, 2009). To determine the role of genetic interaction between JNK2 and beta-catenin in intestinal tumorigenesis and to elucidate JNK2-mediated intestinal carcinogenesis, we crossed the JNK2−/−mouse with Apc+/− mice that carry inactivated Apc allele and develops intestinal tumor due to beta-catenin activation and nuclear accumulation. We found that the introduction of mutant JNK2 into Apc+/− did not increase intestinal tumorigenesis when the mice were fed a defined AIN-76A control diet. However, JNK2 reduction significantly increased animal body weight in the Apc+/−/JNK2+/− and Apc+/−/JNK2−/− mice. Interestingly, JNK2 reduction was synergistic with a Western-style high-risk diet (high fat and phosphate, low calcium and vitamin D)(WD) to accelerate intestinal tumorigenesis. Tumor number was significantly increased from 1.89 (AIN-76A diet) to 3.56 (WD) in the Apc+/−/JNK2+/− mice (P&lt;0.01) and to 4.14 (WD) in the Apc+/−/JNK2−/− mice from 1.92 (AIN-76A diet) (P&lt;0.01), even though there was a slight increase of tumor formation in JNK2 wild-type mice (Apc+/−/JNK2+/+) by such a diet (1.55 v.s. 2.0, p=0.4). Therefore, we concluded that JNK2 might have function in controlling fat metabolism, and that loss of JNK2 increases the risk of obesity, the latter synergists with high-fat diet to increase intestinal tumor susceptibility. This data strongly suggests the important role of JNK2 in intestinal carcinogenesis and the essential of dietary manipulation for cancer prevention in the population if their JNK2 is inactivated. The underlying mechanisms are under investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4163.
Abstract 4164: HBx induced IGF-II expression is essential for hepatic dysplasia formation in mice
Authors: Ha Hye-lin , Shin Hye–Jun , Yu Dae-Yuel 
Published: February 2011

Abstract
HCC is one of the most common cancers in the world. Chronic infection with HBV considered as a major risk factor. Among the four proteins from the HBV genome, HBx is a multifunctional regulatory protein which has been reported to be linked with hepatocellular carcinogenesis. We reported HBx induces liver cancer in transgenic mice.
Among the multistep progress of liver carcinogenesis, enlargement (dysplasia) of the liver considered most critical point of this progression. HBx mice showed dysplasia within 4 weeks, dysplastic nodules and HCA after 6 months and HCC after 9 months of age. In this point we found out different expression pattern of IGF-II in HBx liver compare to wild type. In general this protein hormone predominantly active in fetal liver is strictly down-regulated shortly after birth. HBx mice have an increased liver/body weight ratio as well as cyclinD1 expression compared to wild type mice after 2 weeks. At that point, highly expressed IGF-II in wild mice started to decrease but in HBx mice the IGF-II expression still remained high level. The HBx-HepG2 cell line also has a higher expressed IGF-II level than the Mock-HepG2 cell line. Like in vivo data, the HBx cell line showed fast growth and increased cyclinD1 expression levels. Furthermore we found that abnormal cell growth was inhibited by neutralizing secreted IGF-II in vitro system with treatment of IGF-II antibody. In conclusion, we suggest IGF-II leads to liver dysfunction via over-proliferation of an HBx damaged hepatocyte.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4164.
Abstract 4166: Targeted expression of the Pleomorphic adenoma gene 1 in the pancreas of mice leads to islet hyperplasia
Authors: Declercq Jeroen , Kumar Anujith , Diepen Janna Van , Vroegrijk Irene , Gysemans Conny , Pietro Caterina Di , Voshol Peter , Mathieu Chantal , Ectors Nadine , Van de Ven Wim , Vefaillie Catherine 
Published: February 2011

Abstract
Pleomorphic adenoma gene 1 (PLAG1) encodes a transcription factor that is involved in several human neoplasias such as in pleomorphic adenomas of the salivary glands, lipoblastoma, hepatoblastoma and AML. The oncogenic capacity of PLAG1 has been further demonstrated in vivo in PLAG1 transgenic mice, in which the activation of the PLAG1 expression is Cre-mediated. Targeted expression of PLAG1 in the salivary gland or in the mammary gland leads to pleomorphic adenomas of the salivary glands and adenomyoepitheliomatous lesions of the mammary glands, respectively. Here, we investigated the impact of targeted PLAG1 expression in the pancreas. Pdx1-Cre-mediated targeted expression of PLAG1 in the whole pancreas, leads to islet hyperplasia. Although there was initially a balanced increase in the insulin, somatostatin and glucagon content of the pancreas, in older P1-Pdx1Cre mice the production of insulin and somatostatin far exceeded that of glucagon (82%, 275% and 9% respectively in 1 year old P1-Pdx1Cre mice as compared to littermate Pdx1-Cre mice). This was associated with hyperinsulinemia and an increased ability to dispose glucose in P1-Pdx1Cre mice, and progressive development of severe hypoglycaemia. Only 1/10 one year old mice developed a pancreatic tumor. We also investigated the consequence of overexpression of PLAG1 only in β-cells by using RIP-Cre mice. Similar to P1-Pdx1Cre mice, P1-RIPCre mice displayed islet hyperplasia, hyperinsulinemia and an increased ability to dispose glucose. Nevertheless, in contrast to P1-Pdx1Cre mice, P1-RIPCre mice stay normoglycemic and compensate for the hyperinsulinemia by the development of hepatic insulin resistance. In conclusion our data demonstrates that targeted expression of PLAG1 in the pancreas leads to islet hyperplasia rather than to pancreatic tumor formation.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4166.
Abstract 4178: N-cadherin haploinsufficiency prolongs survival in a genetically engineered mouse model of pancreatic cancer
Authors: Su Yanrong , Li Jifen , Griffith Leeanne , Radice Glenn 
Published: February 2011

Abstract
Cadherin switching (E-cadherin to N-cadherin) associated with epithelial-mesenchymal transition is implicated in the transition from benign tumors to invasive, malignant cancer and the subsequent metastatic dissemination of tumor cells. Although N-cadherin upregulation has been observed in many cancer types including pancreatic ductal adenocarcinoma (PDA), the importance of this cell adhesion receptor in disease progression is not well understood. The concomitant expression of oncogenic KrasG12D and a mutant Trp53R172H allele in the developing murine pancreas results in metastatic PDA that recapitulates the cognate features of human pancreatic cancer providing an excellent animal model to identify genetic changes required for tumor progression. Here we determine the consequences of genetically blocking the switch to N-cadherin in a mouse model of PDA. Two independent N-cadherin mutant alleles were used in these genetic studies. Remarkably, pancreatic cancer mice heterozygous for N-cadherin (n=17) survived 25% longer (177 vs. 142 days, p &lt;0.05) than N-cadherin wild-type mice (n=16). The survival benefit may be due, at least in part, to increased cell death in the N-cadherin heterozygous tumors. Furthermore, cell death was also increased in tumor cell lines isolated from the N-cadherin heterozygous tumors demonstrating a cell-autonomous apoptotic phenotype. Interestingly, tumors lacking N-cadherin (i.e. null) did not show a survival benefit possibly due to compensation by an alternative metastatic promoting molecule(s). In conclusion, our genetic studies indicate that interfering with N-cadherin-mediated adhesion/signaling delays tumor progression, at least in part, by promoting tumor cell death, thus providing further evidence that N-cadherin antagonists may have therapeutic potential for the treatment of pancreatic cancer in humans.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4178.