bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2092: Pathway specific gene profiling analysis reveals potential target genes of the stress oncoprotein LEDGF/p75 in prostate cancer cells
Authors: Basu Anamika , Drame Awa , De Leon Marino , Casiano Carlos A. 
Published: July 2012

Abstract
Chronic inflammation in the prostate microenvironment, with its associated increase in oxidative stress, is critical for prostate carcinogenesis since it leads to DNA mutations and epigenetic changes, as well as deregulation of stress and antioxidant proteins that protect prostate cells against oxidative damage and cell death. The lens epithelium-derived growth factor p75 (LEDGF/p75), an oxidative stress-induced transcription coactivator, is overexpressed in prostate tumors and other tumor types. LEDGF/p75 is emerging as a stress oncoprotein that protects cancer cells against lysosomal cell death and promotes resistance to chemotherapeutic drugs. We hypothesize that the pro-survival function of LEDGF/p75 is associated with its ability to promote the transcriptional activation of protective stress genes. To date, only very few candidate target genes of LEDGF/p75 have been identified in cancer cells. Towards this goal we initiated a stress focused gene profiling analysis of PC3 prostate cancer cells overexpressing or lacking LEDGF/p75, using the Real Time PCR Array System (SABiosciences). We selected an array that contained 80 genes involved in the cellular stress response and antioxidant defense. siRNA oligos targeting the C-terminus of the LEDGF/p75 mRNA sequence were used to induce transient LEDGF/p75 knockdown in PC3 cell. LEDGF/p75 was also stably overexpressed in PC3 cells by transduction with a lentiliviral vector. Both transient siRNA-mediated knockdown and overexpression of LEDGF/p75 were associated with significant changes in the expression of several stress/antioxidant genes, using a cutoff fold change value of 1.5 (P&lt;0.001). We selected for further analysis common genes that were significantly downregulated when LEDGF/p75 was knocked down and upregulated when this protein was overexpressed. These genes are phosphoinositide-binding protein E, cytoglobulin, superoxide dismutase 3, thyroid peroxidase, titin, glutathione transferase zeta1 and albumin. The expression of these genes in response to LEDGF/p75 expression was further validated using real-time RT-PCR. This study identifies candidate stress genes potentially regulated by LEDGF/p75 in PC3 cells, and provides a rationale for investigating the mechanisms by which this emerging stress oncoprotein promotes resistance to lysosomal cell death and chemotherapy in prostate tumor cells.
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 2092. doi:10.1158/1538-7445.AM2011-2092
Abstract 2104: Frequent inactivation of A20 and its prognostic significance in Middle Eastern colorectal carcinoma
Authors: Abubaker Jehad , Bavi Prashant , Uddin Shahab , Jehan Zeenath , Ahmed Maqbool , Al-Sanea Nasser , Abduljabbar Alaa , Ashari Luai H. , Alhomoud Samar , Al-Dayel Fouad , Sultana Mehar , Al-Haqawi Wael , Al-Rasheed Maha , Hassan Nurul , Qadri Zeeshan , George Thara , Prabhakaran Sarita E. , Balde Valorie , Siraj Abdul K. , Al-Kuraya Khawla S. 
Published: July 2012

Abstract
A20, also known as TNF alpha induced protein3 (TNFAIP3), is a tumor suppressor gene and a well-known negative regulator of the NF-kB pathway in hematolymphoid neoplasms. In colorectal carcinoma (CRC), aberrant NF-kB regulation has been associated with poor prognosis and resistance to therapy. However, role of A20 gene in CRC is unknown. Therefore, we sought to elucidate the biological role of A20, mechanism of its inactivation and its prognostic role in colorectal carcinoma. We investigated the genetic and epigenetic abnormalities of A20 gene in CRC. In a tissue microarray cohort of 434 CRC, we studied loss of A20 protein expression by immunohistochemistry and A20 deletions by FISH. We also screened 116 random CRC and 14 CRC cell lines for mutations in A20 gene and A20 promoter methylation. Of the 116 CRC samples, A20 deletions were seen in 15.3% and incidence of A20 mutation was 2.5%; most of the mutations (4/5) were missense mutations. A20 promoter hyper-methylation was seen in 50.8% and was correlated with loss of protein expression (p=0.0079). A20 inactivation, defined as loss or reduced expression of protein was observed in 63% of CRC and A20 inactivation was an independent prognostic marker for poor survival in all CRC. In addition A20 expression retained its prognostic value in the following subgroups: Stage III; Stage II and III; and Stage III and IV. A20 was inactivated in majority of the CRC due to promoter methylation and can be targeted to modulate NF-κb expression.
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 2104. doi:10.1158/1538-7445.AM2011-2104
Abstract 2108: New analogues of benzyl-isothiourea showed Rb-Raf disruption and anti-cancer activity
Authors: Verma Monika , Johnson Jackie , Kovacs Michelle , Singh Sandeep , Wu Xin , Lawrence Nicholas , Sebti Said , Chellappan Srikumar 
Published: July 2012

Abstract
The retinoblastoma tumor suppressor protein Rb, is a vital regulator of the mammalian cell cycle which is inactivated by phosphorylation. We had shown that Raf-1 kinase binds and phosphorylates Rb early in the G1 phase facilitating its subsequent phosphorylation by cyclin dependent kinases. This phosphorlation released transcriptionally active E2Fs from Rb to facilitate S-phase entry. Disruption of Rb-Raf protein-protein interaction could prevent proliferation and angiogenesis, leading to inhibition of tumor growth in mouse models. We had earlier identified an orally active small molecule, Rb/Raf-1 disruptor 251 (RRD-251) that potently and selectively disrupts Rb/Raf-1 but not Rb/E2F, Rb/prohibitin, Rb/cyclin E or Rb/HDAC interactions. Here, we have made efforts to analyze additional analogues of RRD251; we focused on XW-19B and XW-35B. These compounds inhibited Rb-Raf interaction in vitro and in vivo as shown by ELISA and Immunoprecipitation-Western blot analysis. They also inhibited cell viability, proliferation, migration, invasion, angiogenesis and adherence-independent growth of human lung cancer cell lines A549. XW-19B inhibited tumor growth significantly in human A549 xenograft model in nude mice, compared to control while XW-35B showed certain amount of toxicity to animals at 50MPK. Overall, these results showed that Rb-Raf disruptors XW-19B and XW-35B have potential anticancer activity. Thus, selective targeting of Rb/Raf-1 interaction seems to be a promising approach for developing novel chemotherapeutic agents.
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 2108. doi:10.1158/1538-7445.AM2011-2108
Abstract 2116: The Cables1 protein complex couples survival signaling to cell death machinery
Authors: Shi Zhi , Park Hae Ryoun , Du Yuhong , Fu Haian , Khuri Fadlo R. 
Published: July 2012

Abstract
Cables1 is a candidate tumor suppressor and functions as a negative regulator of cell growth through inhibition of Cdks. Indeed, loss of Cables1 expression has been observed with high frequency in many cancers. However, little is known about how Cables1 itself is regulated. Here we report that Cables1 is regulated by a phosphorylation-dependent, 14-3-3-mediated mechanism. Further studies through mutational analysis have led to the identification of two residues of Cables1 that are critical for 14-3-3 binding. These residues of Cables1 serve as a substrate of serine/threonine kinase Akt. Akt could directly bind to and phosphorylate Cables1, recruiting 14-3-3 to the complex. Moreover, Cables1 overepxression induces cell apoptosis and inhibits cell growth in part through stabilizing p21 and decreasing Cdk2 kinase activity. Activated Akt is able to prevent cell apoptosis induced by Cables1. Importantly, the level of phosphorylated Cables1 has been correlated with that of pAkt in human lung cancer patient tissues, supporting a potentially significant event in lung cancer tumorigenesis. Together, our results suggest a dynamic regulatory system by which activated Akt phosphorylates Cables1 and recruits 14-3-3 to neutralize a potent tumor suppressor function.
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 2116. doi:10.1158/1538-7445.AM2011-2116
Abstract 2142: Signaling pathways involved in apoptosis-resistance against doxorubicin analogues in murine mammary cells; Role of protein kinase C delta (PKCΔ)
Authors: Bessone María Inés Díaz , Berardi Damian E. , Campodónico Paola B. , Lothstein Leonard , Todaro Laura B. , Bal de Kier Joffé Elisa D. , Urtreger Alejandro J. 
Published: July 2012

Abstract
In this work we have analyzed whether the overexpression of PKCΔ in murine mammary cells (NMuMG) is able to alter cell death susceptibility to two chemotherapeutic drugs derived from doxorubicin (AD198 and AD288), and evaluate the signaling pathways involved in this process. Similarly to doxorubicin, the mechanism of action of AD288 involves the generation of DNA damage whereas, it has been proposed that AD198 induces apoptosis by activating PKC isoforms, in particular PKCΔ.
By western blot we could determine that NMuMG-PKCΔ cells showed an increase in the activation and/or expression of different molecules and signaling pathways involved in cell survival such as Bcl-2, pBad, PI3K/Akt y NFκB. Therefore PKCΔ overexpression induced an increase in cell death resistance against both ADs (survival: AD198: 80±10% vs. 41±8% and AD288: 90±15% vs. 60±10% in NMuMG-PKCΔ and NMuMG-vector cells respectively).
In order to evaluate the role of PI3K/Akt pathway in cell death resistance induced by both ADs, cells were treated with LY294002, a PI3K inhibitor. The inhibition of this signaling pathway in NMuMG-PKCΔ cells increased 3-fold AD198 cytotoxic effect, whereas did not alter AD288 effect.
The role of NFκB signaling pathway in the resistance against cell death induced by each AD was determined by transient transfection with a variant of its repressor IκB. The inhibition of this signaling pathway significantly increased cell death susceptibility to both drugs (P&lt;0.05 student's t test).
In this work we have demonstrated that the anti-apoptotic signals generated by PKCΔ in NMuMG mammary cells could be reverted by inhibiting PI3K/Akt and/or NFκB signaling pathways. In addition, it was shown that the pathway involved was dependent on the mechanism of action of the cytotoxic drug used.
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 2142. doi:10.1158/1538-7445.AM2011-2142
Abstract 3907: Gene expression profile of aging-related genes in human gastric cancer development
Authors: Kim Han Sang , Kim Sang Cheol , Park Chan Hee , Shin Sang Joon , Ahn Joong Bae , Jeung Hei-Cheul , Chung Hyun Cheol , Roh Jae Kyung , Rha Sun Young 
Published: July 2012

Abstract
Background: Aging process modifies gene expression pattern and might be related to certain disease like cancer. As clinical outcome worsens with age, different molecular behavior of cancer between aging should be elucidated to accomplish future personalized medicine, especially in geriatric cancer patients.
Methods: Primary gastric cancer tissues and corresponding normal mucosa were obtained from 81 patients. cDNA microarray analysis was performed using 14,125 probes. To select differentially expressed genes between aging, multiple regression model considering age, sex, stage, and pathology was applied. Functional study and pathway analysis was performed through database for annotation, visualization and integrated discovery (DAVID) and Ingenuity pathway analysis.
Results: In normal tissues, two hundred and ninety-six genes were determined as aging-related genes that were involved in aging-process relation with mitochondria and ubiquitination. In tumor tissues, sixty-two genes were identified that showed significantly different expression according to age. Twenty genes were up-regulated and forty-two genes were down-regulated. Apoptosis (6 genes), carbohydrate metabolism (4 genes), cell cycle (8 genes), cellular proliferation (7 genes), DNA repair (3 genes), and inflammation (5 genes) were related. In pathway analysis with tumor tissues, gene expression was down-regulated with age in proliferation pathways including growth hormone, PI3K/Akt, TGF-β, and TNFR signaling. Furthermore, genes involved in tumor suppressor pathways involving apoptosis and PTEN were down-regulated in older tumors.
Conclusions: As gastric cancer develops later, carcinogenesis is less dependent from proliferation, but also tumor suppressor pathways. Our results could be one explanation of less chemotherapy response and enhancing defense mechanism is needed in old-age gastric 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 3907. doi:10.1158/1538-7445.AM2011-3907
Abstract 4077: Exposure to bile acids alters intracellular expression of MnSOD in Barrett's esophagus
Authors: Farmer Russell W. , Li Yan , Hill Charles R. St. , Schiffman Suzanne , Harper Nicholas L. , Kang Xinqin , Martin Robert C. 
Published: July 2012

Abstract
Introduction: Oxidative stress secondary to bile acid exposure has been associated with metaplastic degeneration of normal esophageal mucosa into Barrett's Esophagus cells and eventually Esophageal Adenocarcinoma. We have previously reported that the macromolecular response of BE cells to this stress is largely regulated by the expression of Manganese Superoxide Dismutase (MnSOD). As the mitochondrion plays a vital role in MnSOD activation, the purpose of this study was to determine the location and activity of MnSOD within the BE cell after exposure to oxidative stress.
Methods: BE cells were cultured to 80-90% confluence in 75ml flasks. The cells were then exposed for four hours to 0.4mM concentrations of taurocholic acid (TCA) or a 0.4mM 1:1 mixture of bile salts including sodium cholate (CA), sodium deoxycholate (DCA), sodium glycocholate (GCA), and sodium taurocholate (TCA) to mimic natural biliary refluxate. Proteins were extracted and separated into mitochondrial, nuclear, and cytoplasmic fragments followed by western blot analysis. Enzymatic Activity of MnSOD was determined by silencing of other SOD molecules with potassium cyanate. Lethality testing of biliary exposure was performed with MTT assays.
Results: Mitochondrial expression of MnSOD was significantly increased in the cells exposed to a mixture of bile acids vs. TCA and control. This was present on both qualitative and quantitative analyses of Western blots. Cytoplasmic expression of MnSOD was also present and conserved between treated and untreated cells. Control cells lines showed no significant change in baseline MnSOD expression. This expression was confirmed by increased MnSOD activity in the mitochondria of cells exposed to mixed bile. The lethality of mixed bile for Barrett's cells was confirmed by MTT assay, with isolated bile salts and controls having a significantly higher fraction of living cells.
Conclusion: This is the first study to evaluate microcellular MnSOD expression which is increased in BE cells in response to the oxidative stress of bile exposure, specifically in the mitochondrion. Mitochondrial MnSOD activity is increased within the BE cell after exposure to bile. Further investigation is required to determine the potential correlation between bile exposure and BE to adenocarcinoma progression.
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 4077. doi:10.1158/1538-7445.AM2011-4077
Abstract 4078: ANT-ligands small molecules induce apoptosis of cancer cells by inhibiting ATP/ADP translocation
Authors: Borgne-Sanchez Annie , Buron Nelly , Porceddu Mathieu , Jacotot Etienne , Brenner Catherine 
Published: July 2012

Abstract
Since fifteen years ago, the mitochondrion has been progressively recognized as an integrator-coordinator of apoptosis. In this context recent anti-cancer drugs in development are targeting mitochondrial apoptotic machinery to induce tumor cell death. By this strategy, drugs can interact with apoptosis-regulating proteins of Bcl-2 family to trigger Bax/Bak oligomerization and mitochondrial membrane permeabilization. This event conducts to the release of pro-apoptotic factors such as cytochrome c into the cytosol that are required for caspases activation and apoptosis process. In this study, we selected another strategy and investigated the effect of ANT-targeting small molecules to induce cancer cells apoptosis. The adenine nucleotide translocator (ANT) is a mitochondrial protein of the inner membrane involved in the exchange of ADP and ATP between the mitochondrial matrix and the cytosol. Medicinal chemistry approach coupled with in silico studies yield to several small organic compounds, which proved to be specific for ANT and fulfill druggability criteria (good cell penetration and biodisponibility). We identified a family of compounds that inhibited ATP translocation and induced apoptosis by a pathway involving Bax-dependent cytochrome c release and caspases activation. One of the hit compound was optimized to obtain molecules able to induce apoptosis of HT-29 and BxPC3 cells at 100 nM. We are currently investigating which ANT isoform(s) is (are) targeted in cells. In vivo tumor regression experiments will be performed to achieve the proof of concept of ANT-ligands small molecules as an interesting anti-cancer strategy.
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 4078. doi:10.1158/1538-7445.AM2011-4078
Abstract 4081: Sensitivity of gastric cancer cell lines against 2-deoxy-D-glucose is independent of PI3K/mTOR inhibition
Authors: Eder Sandra , Strommer Sabine , Füreder Thorsten , Freitag Rene , Dorn Sebastian , Wacheck Volker 
Published: July 2012

Abstract
2-deoxy-D-glucose (2-DG) is currently studied in Phase I clinical trials as a novel therapeutic strategy for anti-cancer therapy. Several preclinical studies have suggested that the anti-proliferative activity of 2-DG might be linked, amongst others, to the inhibition of the PI3K/mTOR signalling pathway. Blocking the PI3K/mTOR pathway has become a major focus for molecular targeted drug development. In the current study we assessed the biological relevance of PI3K/mTOR signalling for the anti-proliferative activity of 2-DG in gastric cancer cells.
The gastric cancer cell lines (N87, MKN-28, MKN-45) were treated with 2-DG and evaluated for cell proliferation, apoptosis induction, cell cycle arrest, and PI3K/mTOR signalling. Everolimus, a specific mTORC1 inhibitor, was employed as positive control.
Treatment with 2-DG potently suppressed cell proliferation resulting in an up to 300% reduced IC50 in the gastric cancer cell lines. Cell cycle inhibition and apoptosis induction varied substantially among cell lines. However, the distinct 2-DG sensitivity of gastric cancer cell lines was not reflected by any alteration in the PI3K/mTOR signalling pathway. In all cancer cell lines, no major inhibition of pERK and pAKT was observed, whereas both, 2-DG as well as everolimus strongly inhibited phosphorylation of S6. In contrast to 2-DG everolimus induced also a clear inhibition of 4EBP1 phosphorylation.
In conclusion, inhibition of PI3K/mTOR signalling pathway by 2-DG differs from inhibition by everolimus and is not linked with 2-DG anti-proliferative sensitivity in gastric cancer cell lines.
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 4081. doi:10.1158/1538-7445.AM2011-4081
Abstract 4085: Inhibition of rodent mammary carcinogenesis by wheel running and/or dietary energy restriction
Authors: Jiang Weiqin , Zhu Zongjian , McGinley John N. , Zacher Jarrod , Neil Elizabeth , Thompson Henry J. 
Published: July 2012

Abstract
The prevention of breast cancer by the combined effects of physical activity (PA) and dietary energy restriction (DER) has received limited investigation. The objective of this experiment was to determine the inhibitory effects of PA and/or DER on mammary carcinogenesis and associated mechanisms. Female Sprague Dawley rats were injected with 1-methyl-1-nitrosourea (50 mg/kg) and 7 days thereafter randomized to: 1) sedentary control, 2) PA at 3000 revolutions (3.36 km) per day; or the energy balance equivalents of PA: 3) 20% DER or 4) PA at 1500 revolutions per day + 10% DER. In order to investigate the effects of physical activity at a constant intensity, rats were given free access to a motorized activity wheel (55 m/min) with reinforcement of running behavior using a food reward system. The duration of this experiment was 8 weeks. As intended, final body weights of the sedentary control were higher than PA, DER or PA&DER, but the intervention groups had similar final weights. Overall, PA and/or DER reduced mammary cancer incidence, cancer multiplicity, and tumor burden and prolonged cancer latency (p&lt;0.05) in comparison to the sedentary control group. However, the differences in these cancer endpoints among the intervention groups were not statistically different. Experiments are in progress to determine the extent to which host systemic factors and cell autonomous mechanisms are differentially affect by PA, DER, or their combination in this context of energy balance equivalence. Supported by PHS grant CA100693 from the National Cancer Institute.
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 4085. doi:10.1158/1538-7445.AM2011-4085