bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1267: The RING domain of TRAF2 inhibits TNFα-induced cell death independent of NF-κB activation
Authors: Zhang Laiqun , Blackwell Ken , Shi Zhaohui , Habelhah Hasem 
Published: February 2011

Abstract
TNFα is a pleiotropic cytokine that activates both the pro-survival IKK/NF-κB and the pro-apoptotic FADD/caspase-8 pathways. TNF receptor associated factor 2 and 5 (TRAF2/5) contain N-terminal RING domains, and TRAF2/5 RING domain-mediated RIP1 ubiquitination is believed to be essential for NF-κB activation and inhibition of cell death in response to TNFα stimulation. In support of this notion, TRAF2/5 double knockout (TRAF2/5 DKO) cells are sensitive to TNFα-induced apoptosis. In addition, the RING domain-deleted TRAF2 (TRAF2-ΔR) has been widely used in the field as a dominant negative to block TNFα-induced JNK and IKK activation in transient overexpression systems. Here, we report that stable expression of TRAF2-ΔR in TRAF2/5 DKO cells at a physiological level completely restores normal TNFα-induced NF-κB activation, but that it neither restores RIP1 polyubiquitination nor inhibits cell death. We also found that the basal and inducible expression of anti-apoptotic proteins in TRAF2-ΔR-expressing cells is normal, yet these cells remain sensitive to TNFα-induced cell death because anti-apoptotic proteins were not recruited to the TNFR1 complex efficiently. This suggests that two events are required for the inhibition of TNFα-induced cell death: i) NF-κB-dependent expression of anti-apoptotic proteins such as cIAP1/2 and cFLIP; and ii) TRAF2 RING domain-dependent retention of cIAP1 in the TNFR1 complex. Ablation of either event leads to caspase-8 activation and cell death in response to TNFα stimulation. Our data also suggest that RIP1 ubiquitination is not essential for TNFα-induced NF-κB activation.
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 1267.
Abstract 1273: Involvement of PKCδ and NOX4 in reactive oxygen species-mediated tumor resistance to TRAIL-induced cell death
Authors: Choi Kyungsun , Ryu Seungwook , Song Seungjeong , Choi Hyosook , Choi Chulhee 
Published: February 2011

Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family of cytokines, causes apoptosis by caspase activation in various cell types, particularly in transformed cells. Numerous types of tumors are relatively resistant to TRAIL-induced cytotoxicity; however, the reasons for this are not yet fully understood. We report here a new signal transduction pathway involving protein kinase Cδ (PKCδ), NADPH oxidase 4 (NOX4) and reactive oxygen species (ROS), that inhibits caspase-dependent cell death induced by TRAIL ligation in human malignant astrocytoma cells. In our experiments, TRAIL ligation-induced generation of intracellular ROS through caspase-dependent proteolytic activation of PKCδ and subsequent activation of the NOX4 complex. Suppression of intracellular ROS induction using various pharmacological inhibitors or PKCδ- or NOX4-specific RNA interference enhanced the enzymatic activity of caspase-3 by blocking the oxidative modification of its catalytic cysteine residue, resulting in marked augmentation of TRAIL-mediated cell death. In addition, combined treatment with ROS scavengers enhanced TRAIL-induced cytotoxicity in an experimental tumor model. These results collectively indicate that TRAIL-induced activation of PKCδ and NOX4 can modulate TRAIL-mediated apoptosis by promoting oxidative modification of active caspase-3 in a negative-feedback manner.
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 1273.
Abstract 1274: Heterotrimeric stimulatory GTP-binding proteins inhibit cisplatin-induced apoptosis by inducing XIAP in cervical cancer cells
Authors: Cho Eun Ah , Juhnn Yong-Sung 
Published: February 2011

Abstract
Cisplatin (cis-dichlorodiammineplatinum (II)) induces DNA double-strand breaks (DSBs), which are considered as the main cytotoxic damage that induces apoptosis of human cancer cells. Cisplatin was also known to found to inhibit DNA-synthesis and DNA-repair in HeLa cervical carcinoma cells. Recently, we observed that heterotrimeric G proteins modulate apoptosis signaling in several cancer cell lines. In this study, we attempted to investigate the effect of Gαs on apoptosis triggered by cisplatin and its molecular mechanism in HeLa cells. Expression of constitutively active Gαs (GαsQL) decreased the cleavage of caspase-3 and PARP at 24 hr after treatment of HeLa cells with 30 µM cisplatin, indicating that Gαs inhibited cisplatin-induced apoptosis of HeLa cells. Expression of GαsQL increased the expression of XIAP (inhibitor of apoptosis protein), and partially recovered the cisplatin-induced decrease in XIAP. Knock down of Gαs expression by shRNA reduced the expression of XIAP and augmented cisplatin-induced apoptosis. This study shows that Gαs can protect apoptosis triggered by cisplatin by up-regulation of XIAP in HeLa cervical cancer cells. These results suggest that Gαs signaling may contribute carcinogenesis and progression of cervical 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 1274.
Abstract 1275: Expression of Nur77 induced by an n-butylidenephthalide derivative promotes apoptosis and inhibits cell growth in oral squamous cell carcinoma
Authors: Liu Po-Yen , Su Yi-Chang 
Published: February 2011

Abstract
Background: In spite of numerous advances, the 5-year survival rate for head and neck squamous cell cancer has remained largely stagnant, and few new anti-tumor drugs have been developed for oral squamous cell carcinoma (OSCC). PCH4 ((Z)-N-(2-(dimethyl-amino) ethyl)-2-(3-((3-oxo-isobenzofuran-1(3H)-ylidene) methyl) phenoxy) acetamide), a derivative of n-butylidenephthalide (BP), was investigated for anti-tumor effects on OSCC.
Aim: The aim of this study was to investigated the mechanism of Nur77 translocation induced by PCH4
Methods: OSCC cells were treated by PCH4 in vitro and in vivo. The Nur77 translocation was detection by western blotting, immunohistochemistry and immunocytochemistry.
Results: PCH4 promoted Nur77 translocation from the nucleus to the cytoplasm and induced cell apoptosis in OSCC cells. When Nur77 translocation was prohibited by Nur77 short interfering RNAs, the degree of tumor apoptosis caused by PCH4 was significantly alleviated. Within the MAPK pathway, PCH4 induced only JNK phosphorylation. Furthermore, treatment with a JNK inhibitor significantly reduced PCH4-induced apoptosis (p&lt;0.05) and decreased PCH4-induced Nur77 expression (p&lt;0.05). In a xenograft animal model, administration of PCH4 showed similar anti-tumor effects in OSCC cells that were dose dependent. Immunohistological staining showed similar effects on Nur77 expression and apoptosis in xenografts.
Conclusion: We have demonstrated that OCSS cells are sensitive to PCH4 and that Nur77 protein translocation from the nucleus to the cytoplasm might be associated with the induction of apoptosis by PCH4. These results, both in vitro and in vivo, indicate that PCH4 may serve as a potential anti-tumor drug for OSCC therapy.
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 1275.
Abstract 1276: TRAIL-induced p38 activation responsible for increases of Akt catalytic and Invasive activity
Authors: Sun Bo K. , Kim Joo-Hang , Kim So Y. , Oh Seeun , Choi Hye J. , Sohn Joo-Hyuk , Lee Yong J. , Song Jae J. 
Published: February 2011

Abstract
In this paper, we demonstrate that TRAIL-induced p38 activation is responsible for the increases of Akt catalytic activity and invasive activity. For the confirmation of increases of Akt catalytic and invasive activity induced by TRAIL-induced p38 activation, immune complex kinase assay and invasion assay was used. Previously, we observed that TRAIL induces acquired TRAIL resistance with increased Akt phosphorylation resulting from Src-PI3K-Akt signaling pathways mediating by c-Cbl. c-Cbl, an ubiquitously expressed cytoplasmic adaptor protein was shown to be involved in the rapid degradation of TRAIL receptors and simultaneously in the Akt phosphorylation during TRAIL treatment. However, Akt phosphorylation did not have an exclusive role for acquired TRAIL resistance. Like Akt catalytic activation during metabolic oxidative stress, TRAIL induced dramatically Akt catalytic activation in TRAIL-sensitive cells, whereas TRAIL did not induce Akt catalytic activation in TRAIL-resistant cells, suggesting Akt catalytic activation during TRAIL-induced apoptosis is likely to have a role of compensation for cell homeostasis. Our studies also reveal that p38 activation during TRAIL treatment is responsible for the increases of Akt catalytic and invasive activity.
Bo K. Sun and Joo-Hang Kim are equally contributed to this work.
Correspondence: Jae J Song (jjs109@yuhs.ac)
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 1276.
Abstract 1277: Differential roles of TRAIL death receptors during TRAIL-induced signaling pathways
Authors: Kim So Y. , Oh Seeun , Sun Bo K. , Choi Hye J. , Sohn Joo-Hyuk , Song Jae J. , Kim Joo-Hang 
Published: February 2011

Abstract
In this paper, we demonstrate that TRAIL death receptors (DR4, DR5) have their own distinctive function during TRAIL treatment. For the examination of each receptor's role, FACS analysis, biotin labeling to plasma membrane and siRNA technique were used. Previously, we have shown that TRAIL has induced anti-apoptotic signals as well as apoptotic signals. Here, we investigated whether TRAIL death receptors (DR4 and DR5) have their own unique function. In TRAIL-sensitive cell line (DU-145), TRAIL induced much more rapid degradation of DR4 than that of DR5. On the other hand, in TRAIL-resistance cell line (SK-BR-3) with higher level of ErbB2/pAkt, DR5 was rarely expressed, while DR4 was distinctively expressed. We also have shown that relatively much more amount of c-Cbl in SK-BR-3 has played a role of supplying additional pAkt which can be also persistently provided by ErbB2. These phenomena are confirmed by knock down of c-Cbl expression using adenovirus expressing si-c-Cbl. Taken together, we suggest that DR4 functions to transmit apoptosis signals with a favor for anti-apoptosis signals, whereas DR5 functions to transmit apoptosis signals without a favor for anti-apoptosis signals.
Correspondance: Jae J. Song (jjs109@yuhs.ac) and Joo-Hang Kim (kjhang@yuhs.ac)
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 1277.
Abstract 1280: Inhibition of cellular FLICE-inhibitory protein and induction of Death Receptor 5 expression is a major component of δ- tocotrienol-induced apoptosis in pancreatic cancer cells
Authors: Zhang Anying , Francois Rony A. , Hodul Pamela J. , Husain Kazim , Shivers Steven , Coppola Domenico , Sebti Said M. , Malafa Mokenge P. 
Published: February 2011

Abstract
Background: Previous pre-clinical studies have demonstrated that δ-tocotrienol, is the most bioactive natural vitamin E compound against pancreatic cancer. δ-Tocotrienol induces growth arrest and apoptosis in several human pancreatic cancer cell lines; however, the underlying mechanism remains unknown. In this study, we evaluated the role of the extrinsic and intrinsic apoptotic signaling pathways in δ-tocotrienol-induced apoptosis. Also, we investigated the modulation of cellular FLICE-inhibitory protein (c-FLIP) and death receptor 5 (DR5) by δ-tocotrienol, and the involvement of c-FLIP down-regulation and DR5 up-regulation in δ-tocotrienol-induced apoptosis.
Methods: We examined δ-tocotrienol induced apoptosis in human pancreatic cancer cell lines in vitro and in vivo. We used western blot and immunohistochemistry to determine the expression of DR4, DR5, Caspase 8, Caspase 9, Caspase 3, c-FLIP, and PARP. The effect of combination treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and δ-tocotrienol was also determined. We examined the cellular effects of DR5 knockdown using small interfering RNA oligonucleotides, and c-FLIP overexpression using c-FLIP cDNA, on δ-tocotrienol-induced apoptosis using various assays.
Results: Delta-tocotrienol activated caspase-8 and its downstream caspases but not caspase-9. Caspase-8 specific inhibitor abrogated δ-tocotrienol-induced apoptosis whereas caspase-9 specific inhibitor did not, indicating that δ-tocotrienol induces caspase-8 -dependent apoptosis. c-FLIP was rapidly down-regulated by δ-tocotrienol in all of the tested cell lines. Delta-tocotrienol up-regulated DR4 and DR5 significantly and enhanced TRAIL-induced apoptosis. Enforced expression of ectopic c-FLIP, and DR5 knockdown partially abolished δ-tocotrienol-induced apoptosis. δ-Tocotrienol inhibition of pancreatic tumor growth in SCID mice was associated with significant induction of apoptosis, activation of caspase 8, and down-regulation of c-FLIP expression.
Conclusion: We conclude that DR5 up-regulation and c-FLIP down-regulation contributes to δ-tocotrienol-induced apoptosis in pancreatic cancer cells.
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 1280.
Abstract 1283: Chromosome 19 amplification and the consequent NOTCH and VEGF pathways over-activation are associated with malignant glioma poor outcome
Authors: Assem Mahfoud , Sibenaller Zita , Agarwal Supreet , Al-Keilani Maha , Alqudah Mohammad , Marner Joyce , Ryken Timothy C. 
Published: February 2011

Abstract
Malignant gliomas are the most frequent type of primitive brain tumors. Their outcome did not improve despite new therapeutics, resulting mainly from their genetic heterogeneity and complexity. By using genome-wide explorations we have recently identified, for the first time, that chr.19 amplification correlates with a grim therapeutic outcome.
The aim of our current study is to investigate the significance of the chromosome 19 genetic signature. To narrow the search for specific genes or pathways that may be responsible for this adverse outcome, we selected genes located on chromosome 19 and focused on those that were statistically significantly deregulated between tumors and non tumor tissues. We identified 41 genes which mapped to chromosome 19. The most significant genes are NOTCH3 and HIF3α. These genes belong to NOTCH and VEGF pathways and play important roles in angiogenesis. Using quantitative real time PCR, RT-PCR and immunobloting, we further analyzed the level of gene expression of critical elements of these pathways and confirmed that NOTCH3 was amplified in primary glioma cell lines that harbor gains of chr.19. This increase has been shown at both the mRNA and protein levels. Moreover, NOTCH ligand, and other constituents of the pathways (DLL3, SHC3, NOTCH4) were also activated in these particular cell lines. Further, HIF3α was also activated in our conditions whereas HIF1α, the other player of HIF transcriptional pathway, was down regulated. These over-expressions were accompanied by a parallel VEGF activation in these cell lines.
This novel genetic signature may lead to critical insights into diagnosis, classification, prognosis, and prediction in improving therapeutic strategies and outcome based on the genetic makeup of the tumor.
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 1283.
Abstract 129: Synthetic lethality induced by loss of PKC delta and mutated Ras
Authors: Chen Changyan , Zhu Tongbo , Chen Lihua , Tsuji Takanori 
Published: February 2011

Abstract
Table of ContentsSynthetic Lethality Induced by Loss of PKC d and Mutated RasAbstract
Synthetic Lethality Induced by Loss of PKC δ and Mutated Ras
Tongbo Zhu,* Lihua Chen,* Wei Du, Takanori Tsuji, and Changyan Chen
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
Abstract
Synthetic lethal interaction between oncogenic Ha-ras and loss of PKC has been demonstrated. Recently, we reported that the concurrent knockdown of PKC α and β, via upregulating PKC δ, sensitizes cells with aberrant Ras signaling to apoptosis. As the continuation of the study, using the shRNA, we demonstrate that loss of PKC δ causes a lethal reaction in NIH3T3/Hras or prostate cancer DU145 cells that overexpress JNK. In this apoptotic process, PKC α and β are upregulated, and then associated with RACK1 (an adaptor for activated PKC) and JNK. Immunoblotting analysis shows that JNK is phosphorylated, accompanied with caspase 8 cleavage. The inhibition of JNK abrogates this apoptotic process triggered by PKC δ knockdown. Interestingly, without blocking PKC δ, the concurrent overexpression of wt- or CAT-PKCα and β is insufficient to induce apoptosis in the cells. Together with our previous findings, the data suggest that PKC α/β and δ function oppositely to maintain a balance that supports cells expressing v-ras to survive and prevents them from being eliminated through oncogenic stress-induced apoptosis.
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 129.
Abstract 1290: O6-methylguanine-methyltransferase modulates glioblastoma angiogenesis and invasion
Authors: Chahal Manik , Sabri Siham , Xu Yaoxian , Famulski Konrad , Murray David , Abdulkarim Bassam 
Published: February 2011

Abstract
Background: Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults. Approximately 50% of GBM patients are resistant to standard therapy with temozolomide (TMZ) because their tumors express the DNA repair protein O6-methylguanine methyltransferase (MGMT), which repairs tumoral DNA damage induced by TMZ. GBM, a highly vascularized tumor, consistently displays a locally invasive phenotype, which contributes to biological aggressiveness and clinical recurrence. Therefore, use of the anti-angiogenic and anti-invasive agent sunitinib malate could be a promising strategy for GBM treatment. We showed that sunitinib-based treatment significantly improved the response of MGMT-positive, but not MGMT-negative, cells and this differential effect was reversed upon MGMT depletion with O6-benzylguanine. In the present study, we investigated the relationship between the expression of MGMT and the angiogenic and invasive profile of GBM cell lines.
Experimental Design: We performed microarray gene expression analysis and quantitative real-time RT-PCR and analyzed the differential expression of transcripts in GBM cell lines with differential expression levels of MGMT: U87 empty vector (MGMT-negative), its counterpart U87/MGMT (MGMT-positive) (stable transfection), and T98G (constitutively expressing MGMT). We also investigated the effect of MGMT expression on GBM angiogenesis by assessing vascular endothelial growth factor (VEGF) secretion and the ability of growth factors secreted in the GBM conditioned media to induce endothelial tube formation in vitro, and the effect of MGMT expression on GBM invasiveness by examining F-actin organization, and migration and invasion in vitro.
Results: The gene chip microarray showed differential mRNA expression of transcripts involved in angiogenesis, invasion, and response to sunitinib in U87/MGMT cells compared to U87/EV cells. These results were confirmed for several transcripts by quantitative real-time RT-PCR or western blotting. Additionally, we also showed that MGMT-positive cells have reduced angiogenic and invasive potential compared to MGMT-negative cells based on decreased VEGF bioavailability, decreased endothelial tube formation, altered morphology, and decreased invasion and migration in vitro.
Conclusion: Our study is the first to show a direct link between MGMT expression and decreased angiogenicity and invasiveness of GBM cells. This altered phenotype may account for the preferential in vitro efficacy of sunitinib malate in MGMT-positive GBM cell lines. Our data provide the rationale to further investigate the role of MGMT in the regulation of the angiogenic and invasive profile of GBM.
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 1290.
Abstract 1291: The neurotransmitter dopamine normalizes tumor neo-vessels by modulating G protein coupled receptor signaling in the cells of tumor microenvironment
Authors: Chakroborty Debanjan , Sarkar Chandrani , Yu Hongmei , Bakshi Shubham , Dasgupta Partha Sarathi , Basu Sujit 
Published: February 2011

Abstract
Tumor neo-vessels, unlike the normal are disorganized, tortuous and leaky. Such dysfunctional blood vessels within the tumors pose significant obstacle for the proper delivery of anticancer drugs into the tumor tissues and response to radiation. Thus normalization of these tumor neo-vessels by different approaches has shown to improve the therapeutic efficacies of conventional anti-neoplastic drugs and radiation therapy. We here show for the first time that the neurotransmitter dopamine normalizes tumor blood vessels in mice bearing orthotopic human prostate cancer by manipulating the cellular components of the tumor microenvironment through G protein coupled receptor signaling. This result is significant because dopamine or dopamine like drugs can be utilized synergistically with either anti-cancer drugs or radiation for the treatment of cancer patients.
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 1291.