bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4980: Age dependent carcinogenic susceptibility of rat liver is related to potential of gap junctional intercellular communication
Authors: Naiki-Ito Aya , Asamoto Makoto , Takahashi Satoru , Shirai Tomoyuki 
Published: August 2012

Abstract
Cancer incidence rises with age, thus, it seems that advancing age is one of the most important risk factors for malignancy. Several factors have been implicated, like DNA alterations. However, there is little experimental evidence to establish the link between aging and carcinogenesis. Gap junctions have important roles in the maintenance of tissue homeostasis and the control of cell growth and differentiation. Connexins are subunits of gap junction channels, which allow intercellular exchange of small molecules, such as ions, second messengers, and cellular metabolites between contacting cells. In the liver, connexin 32 (Cx32) is a major gap junction protein. We previously demonstrated that transgenic rats carrying a dominant negative mutant of Cx32 (Cx32ΔTg) have much decreased capacity for gap junctional intercellular communication (GJIC), and increased susceptibility to diethylnitrosamine (DEN)-induced hepatocarcinogenesis as compared to littermate wild-type (wt) rats. In order to evaluate the age-dependent susceptibility to DEN-induced hepatocarcinogenesis, male Cx32ΔTg and wt rats at 10, 30 or 85 week-old (wk-old) were given a single intraperitoneal administration of DEN (40 mg/rat) and sacrificed 12 weeks later. The number and area of glutathione S-transferase placental form (GST-P)-positive preneoplastic foci were significantly increased in the liver of 10 and 30 wk-old Cx32ΔTg rats compared with age-matched wt. However, in the 85 wk-old rats, both Cx32ΔTg and wt rats had similarly large number and area of GST-P-positive foci, and the difference was not significant. In accordance with these results, the lack of a difference at 85 weeks may be supposed to the initial lower levels of Cx32 and GJIC function in older wt rats. To confirm this hypothesis, we examined alteration of GJIC function with age in the livers of wt type rats at 10, 40, 70 and 100 wk-old. Interestingly, function of hepatic GJIC was gradually reduced, and protein and mRNA expression of Cx32 were also decreased with aging in wt rats. In summary, the present study shows that GJIC function is decreased with aging in rats, and it may cause promotion of hepatocarcinogenesis in older rats. In addition, Cx32ΔTg may be a good model to study roles of gap junctions in aged liver.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4980. doi:1538-7445.AM2012-4980
Abstract 4981: NADPH oxidase is a novel target of delphinidin to inhibits UVB-induced MMP-1 expression in human dermal fibroblasts
Authors: Lim Tae-Gyu 
Published: August 2012

Abstract
Ultraviolet (UV) induced ROS production is considered a major cause of photoaging via abnormal expression of matrix metalloproteinase (MMP)-1 and NADPH oxidase (NOX) is a key enzyme of endogenous ROS production. Here, we investigated the anti-photoaging effect of delphidin, a major anthocyanin found in berry, beans, and red wine, and its molecular target in UVB-induced MMP-1 expression using primary cultured human dermal fibroblast. Delphinidin inhibited UVB-induced MMP-1 expression in human dermal fibroblasts. UVB-induced MKK4-JNK1/2, MKK3/6-p38, and MEK-ERK1/2 phosphorylation were suppressed by delphinidin. In addition, quantification of ROS stained with the 2′,7′-dichlorofluorescein diacetate (DCF-DA) dye showed that delphinidin significantly inhibited UVB-induced ROS production. Delphinidin significantly inhibited UVB-induced NOX activity. Interestingly, the inhibitory effect of delphinidin on UVB-induced NOX activity was stronger than apocynin, a pharmaceutical NOX inhibitor. Fractioned cell analysis results using a western blot assay showed that delphinidin strongly suppressed UVB-induced P47phox, a NOX subunit, translocation from the cytosol to the membrane. Delphinidin produced similar effects with apocynin on UVB-induced MMP-1 expression. Pull down assays showed that delphinidin directly bound to P47phox. Collectively, our results suggest that NOX is a potential target of delphinidin in the suppression of UVB-induced MMP-1 expression in human dermal fibroblasts.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4981. doi:1538-7445.AM2012-4981
Abstract 4983: Correlation telomere shortening in chronic lymphocytic leukemia cells with oxidative stress and dysregulation of shelterin proteins
Authors: Ishdorj Ganchimeg , Mai Sabine , Zang Yunli , Gibson Spencer B. , Johnston James B. 
Published: August 2012

Abstract
Telomeres are important in maintaining the integrity of the chromosomes. A series of shelterin proteins (TRF1, TRF2, RAP1, POT1a and b, TIPP1 and TIN2), are involved in the maintenance and synthesis of telomeres. In chronic lymphocytic leukemia (CLL), the telomeres are shorter than in normal B cells, with very short telomeres being associated with poor survival. The mechanism for this telomere shortening has been evaluated in the present study. We demonstrated in 150 CLL patients using a Q-RT-PCR assay that the median telomere length was similar in mutated IgVH (Mu-IgVH) cases as in normal B cells, but was significantly shorter in unmutated (Un-IgVH) cases. However, there was considerable variation and overlap in telomere length between the groups. In addition, telomere length was found to shorten in both IgVH mutated and unmutated groups when patients were sequentially followed over years indicating that telomere shortening was an ongoing process. When lymphocytes were stimulated and the telomeres evaluated in metaphase by Q-FISH, telomere length shortening affected all chromosomes equally. To determine if telomere shortening in CLL cells was related to increased free radical formation, we measured plasma lipid peroxidation level (Lipid Hydroperoxide (LPO) assay, Cayman) and DNA breaks (gamma H2AX). As compared to normal B cells, there was increased lipid peroxidation and DNA breaks in both mutated and unmutated CLL cells. When cells were treated with N-acetyl-L-cysteine to scavenge free radicals, there was a decrease in DNA breakage. To assess, whether these changes were associated with alterations of the shelterin complex, protein levels of the shelterins were measured. TRF1 and TRF2 protein levels were increased in all patients compared to normal B cells. TRF2 was also increased in the cytoplasm of CLL cells. Following drug induced apoptosis in CLL cells TRF2 levels decreased but not TRF1 levels. In summary, these studies suggest that the short telomeres in CLL may be related to increased oxidative stress in these cells. TRF1 and TRF2 levels were increased in CLL cells regardless of telomere length suggesting that abnormalities in these proteins may also be involved in telomere shortening. Ongoing studies are evaluating the mechanisms responsible for the shelterin changes in CLL cells and whether altering the levels of these proteins can influence cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4983. doi:1538-7445.AM2012-4983
Abstract 4984: Phosporylation of eIF4E confer resistance to cellular stress
Authors: Cajal Santiago Ramon y , Aasen Trond , Martínez Alba 
Published: August 2012

Abstract
Eukaryotic initiation factor (eIF) 4E mediates eIF4F association with the mRNA 5′ cap structure and is an essential factor for canonical protein translation. eIF4E can act as an oncogene when overexpressed in cell lines and high levels of eIF4E and phosporylated peIF4E have been described in a large number of human tumors. eIF4E has also been described as a component of cytoplasmic stress granules and processing bodies. Importantly, non-phosphorylated 4E-BP1 (often in response to stress) binds eIF4E to suppress protein translation. We demonstrated previously that high levels of peIF4E were associated with resistance to this suppressor effect in carcinoma cell lines. Because the role of peIF4E is not yet well established, we evaluated the role of eIF4E phosphorylation on in vitro stress resistance. Breast carcinoma cell lines (MDA-MB 231, MBA- MB 468 and HeLa cells) and an immortalized human keratinocyte cell line (HaCaT) were infected with retrovirus expressing wild type, hyperphosporylated (S209D) or hypophosporylated (S209D) mutants of eIF4E. Cells were subjected to different types of stress including oxidative (Arsenite), nutrient starving and cisplatin treatment. Immediate and long term response to stress was evaluated using colony formation, MTT cell proliferation assays, co-inmunoprecipitation and immunofluorescence microscopy. A significantly greater recovery after all forms of stress was observed in all the cell lines expressing hyperphosporylated eIF4E-S209D. After treatment with arsenite there was an increase of peIF4E, 4E-T and Hur and importantly higher increase of levels of Hur, CyclinD1, Mcl-1 and eIF4G in eIF4E-S209D expressing cells. Under normal condition we observed a unique colocalitzation of 4E-T and eIF4E-S209D in cytoplasmic bodies. This complex colocalize with Ago2 but not with markers of the stress granules (TIA-1) and processing bodies (DCP1A). By co-immunopreciptation, we observed that peIF4E binds to its carrier protein 4E-T, Ago2 and Hur. Conclusions: Phosphorylated eIF4E confer resistance to several stress conditions, including oxidative stress, DNA damage and nutrient deprivation. The fact that there was a relevant and significant increase of proteins such as Cyclin D1, Mcl-1 and Hur suggests that phosporylated eIF4E has an important role in selectively stimulating RNA translation under stress conditions, possibly via the formation of a unique type of 4E-T/peIF4E cytoplasmic bodies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4984. doi:1538-7445.AM2012-4984
Abstract 4987: Non-targeting siRNA induces NPGPx expression to cooperate with exoribonuclease XRN2 for releasing the stress
Authors: Wei Pei-Chi 
Published: August 2012

Abstract
Short interfering RNAs (siRNAs) target specific mRNAs for their degradation mediated by RNA-induced silencing complex (RISC). Persistent activation of siRNA-RISC frequently leads to non-targeting toxicity. However, how cells mediate this stress remains elusive. In this communication, we found that the presence of non-targeting siRNA selectively induced the expression of an ER-resident protein, non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), but not other ER-stress proteins including GRP78, Calnexin, and XBP1. Cells suffering from constant non-targeting siRNA stress grew slower and prolonged G1 phase, while NPGPx-depleted cells accumulated mature non-targeting siRNA and underwent apoptosis. Upon the stress, NPGPx covalently bound to exoribonuclease XRN2, facilitating XRN2 to remove accumulated non-targeting siRNA. These results suggest that NPGPx serves as a novel responder to non-targeting siRNA-induced stress in facilitating XRN2 to release the non-targeting siRNA accumulation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4987. doi:1538-7445.AM2012-4987
Abstract 4990: PP2A signaling is overridden by MEK/ERK activity leading to suppression of Bim and protection of melanoma cells from ER stress-induced apoptosis
Authors: Tay Kwang Hong , Tseng Hsin-Yi , Jing Lei , Jiang Chen Chen , Ye Yan , Thorne Rick , Liu Tao , Hersey Peter , Zhang Xu Dong 
Published: August 2012

Abstract
Endoplasmic reticulum (ER) stress triggers apoptosis by activating Bim in diverse types of cells. This involves dephosphorylation of Bim by protein phosphatase 2A (PP2A). However, melanoma cells are largely resistant to ER stress-induced apoptosis, indicating that Bim activation is suppressed in melanoma cells undergoing ER stress. We show here that this is due to increased activation of MEK/ERK signaling that overrides the PP2A activity leading to enhanced Bim phosphorylation and subsequent proteosomal degradation. Upon pharmacological ER stress, the Bim protein expression was rapidly downregulated after an initial increase, despite its sustained upregulation at the transcriptional level. Although PP2A exerted the dephosphorylating effect on BimEL, its activity appeared to be superseded by increased activation of MEK/ERK signaling that led to enchanced phosphorylation and accelerated turnover of the protein. Moreover, in contrast to its upregulation by ER stress in MCF-7 and HEK293 cells, PP2A was downregulated in melanoma cells undergoing ER stress. Pharmacological activation or enforced expression of PP2A decreased ERK and Bim phosphorylation, up-regulated Bim expression, and rendered melanoma cells sensitive to ER stress-induced apoptosis. Notably, instead of direct interaction with Bim, PP2A reduced Bim phosphorylation indirectly by dephosphorylating ERK in melanoma cells. Together, these results identify a key resistance mechanism of melanoma cells against apoptosis induced by ER stress.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4990. doi:1538-7445.AM2012-4990
Abstract 4992: SPARC overexpression induces ER stress leading to autophagy-mediated apoptosis in neuroblastoma cells
Authors: Sailaja G. S. , Bhoopathi Praveen , Gorantla Bharathi , Tsung Andrew J. , Rao Jasti S. 
Published: August 2012

Abstract
Neuroblastoma is the most common extracranial solid tumor affecting children. Long-term survival for children (older than 18 months of age) with advanced disease is poor despite aggressive multimodal therapy. Normal cellular apoptosis is affected in multiple ways in a variety of diseases, including cancer. Our earlier studies showed that SPARC overexpression induced autophagy-mediated apoptosis in PNET cells. In the present study, we attempt to determine the signaling cascade associated with initiation of autophagy and apoptosis as a result of SPARC overexpression in combination with radiation. As demonstrated by TUNEL assay, neuroblastoma cells showed increased apoptosis with the combination treatment as compared to treatment with either SPARC or radiation alone. In corroboration, we also observed activation of caspase 3, and cleavage of PARP and Bid as determined by Western blotting. The combination treatment triggered endoplasimic reticulum (ER) stress and thereby an unfolded protein (UPR) response. This was apparent with the activation of stress receptors, pancreatic ER kinase (PERK) and inositol-requiring enzyme (IRE 1), as shown by western blotting. ER stress led to mitochondrial dysfunction through activation of eukaryotic initiation factor 2α (eIF2 α; another ER resident protein). In addition, we demonstrate that overexpression of SPARC induced IRE-JNK activation, leading to induction of the transcription factor CHOP. Inhibition of ER stress (or JNK activation) led to inhibition of autophagy-mediated apoptosis as demonstrated by decreased levels of LC3-II, and cleavage of caspase 3, PARP and Bid. Taken together, these results demonstrate the involvement of ER stress in regulating autophagy-mediated apoptosis in neuroblastoma cells treated with radiation and SPARC overexpression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4992. doi:1538-7445.AM2012-4992
Abstract 4993: IRE1-XBP1 branch of UPR is involved in tumor angiogenesis
Authors: Wang Yugang , Polverini Peter , Alam Goleeta , Ning Yu , Nör Jacques 
Published: August 2012

Abstract
The Unfolded Protein Response (UPR) is activated when the endoplasmic reticulum (ER) in tumor cells is subjected to environmental stress. We and others have previously shown that the eIF2α- PERK-ATF4 pathway, one of three of UPR pathways is involved in tumor angiogenesis by transcriptionally regulating the production of angiogenic mediators such as VEGF. However, role of other UPR pathways in tumor angiogenesis still remains to be elucidated. In this study we examined the role of the IRE1-XBP1 UPR pathway in promoting production of tumor-derived proangiogenic mediators. Upon ER stress IRE1 splices XBP1 into an active transcription factor that induces expression of several target genes. We used the gene-silencing approach in the oral squamous carcinoma cell line UM-SCC-81B to determine the effects of XBP1 knockdown on key angiogenic mediators. We were able to achieve over 80% knockdown of XBP1. mRNA levels of both EDEM1 and Grp78, downstream targets of XBP1 were also significantly inhibited confirming an efficient knockdown. UM-SCC-81B control cells as well as UM-SCC-81B-XBP1 knockdown cells were initially treated with low glucose (5mM) for 24 h to induce UPR. Next, mRNA and protein levels of VEGF were determined using Real-Time PCR and ELISA respectively. We observed a 45% decrease in VEGF mRNA levels and around 36% decrease in VEGF protein levels of UM-SCC-81B-XBP1 knockdown cells upon ER stress. Additionally, we detected a significant decrease in the transcription of several other key angiogenic mediators such as FGF2, IL6, IL8 and CTGF (p&lt;0 .05) in UM-SCC-81B-XBP1 knockdown cells compared to control cells. These results suggest that the IRE1-XBP1 pathway of the UPR promotes tumor angiogenesis through modulating expression of proangiogenic mediators.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4993. doi:1538-7445.AM2012-4993
Abstract 4994: An integrated stress response activator causes cellular senescence and inhibits growth in multiple tumor cell types
Authors: Sayers Carly M. , Koong Albert C. , Koumenis Constantinos 
Published: August 2012

Abstract
The Integrated Stress Response (ISR) is a program elicited by mammalian cells to attenuate global translation in response to a variety of stressors. There are four branches of the ISR, including those mediated by PERK, which responds to endoplasmic reticulum stress, and GCN2, which is activated by amino acid deprivation. Activation of these kinases ultimately leads to translational upregulation of the transcription factor ATF4, which modulates the expression of genes involved in amino acid transport and synthesis, oxidative stress, and differentiation. Complete abrogation of the ISR or its overactivation by pharmacological agents in the presence of hypoxic or nutrient stress has been shown to lead to cell death. Here, we employed a small molecule screen to identify modulators of ATF4 expression via a reporter construct with the 5′-UTR of ATF4 fused to the luciferase gene. From this screen, a compound with ATF4-activating properties was identified. Multiple assays have been used to characterize the effects of this drug, referred to as E235, on both transformed and normal cells. Specifically, we have shown that E235 induces the ISR in a dose-dependent manner in tumor cell lines (HT1080 fibrosarcoma, B16F10 melanoma) but not in normal human diploid cells. The drug also reduces cell viability and proliferation at low μM concentrations, which does not appear to be dependent on apoptosis. By performing live cell microscopy, we observed that after prolonged (&gt;24h) treatment with 1μM E235, the majority of cells displayed senescence-like morphology. This was confirmed by additional experiments, such as staining for senescence-associated β-galactosidase activity and immunoblotting for the upregulation of the cdk inhibitor p21. Future experiments will focus on establishing the roles of ATF4, p21 and p53 in E235-mediated senescence.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4994. doi:1538-7445.AM2012-4994
Abstract 4995: Glucose-regulated protein 78 regulates crosstalk between apoptosis and autophagy to determine antiestrogen responsiveness
Authors: Cook Katherine L. , Shajahan Ayesha N. , Jin Lu , Warri Anni , Hilakivi-Clarke Leena A. , Clarke Robert 
Published: August 2012

Abstract
While over 70% of breast cancers express estrogen receptor α (ER+), drugs targeting these receptors such as Tamoxifen (TAM) or Faslodex (fulvestrant, ICI) often fail to cure these patients. Many ER+ patients fail to respond (de novo resistance) or lose drug responsiveness (acquired resistance), making endocrine resistance a major clinically relevant problem. The molecular mechanisms of endocrine therapy resistance still remain unclear. We show that antiestrogen resistant cells with an acquired resistant phenotype overexpress glucose-regulated protein 78 (GRP78), which is not observed in de novo resistance. Moreover, we show increased expression of GRP78 in MCF7/LCC9 (estrogen independent, ICI resistant, TAM cross-resistant) when compared to the MCF7/LCC1 (estrogen independent, TAM and ICI sensitive) breast cancer cells and tumors. These data reflect the response of aromatase inhibitor resistant breast cancers to second line antiestrogen therapy, and further support the hypothesis that antiestrogen resistance and estrogen independence are separate phenotypes. Targeting GRP78 with RNAi restored antiestrogen sensitivity in endocrine therapy resistant cells (MCF7-RR and MCF7/LCC9), whereas expressing GRP78 cDNA conferred resistance on antiestrogen sensitive breast cancer cells (MCF7 and MCF7/LCC1). We show that GRP78 integrates cellular signaling to inhibit apoptosis (as determined by cleaved caspase-7, cleaved PARP, and annexin V staining) and stimulate prosurvival autophagy (as determined by LC3-II, p62, and GFP-LC3 punctate). Moreover, GRP78-stimulated autophagy is dependent on TSC2/AMPK-mediated mTOR inhibition. Endocrine resistance induced by GRP78 overexpression is prevented through an inhibition of autophagy by ATG5 knockdown, while caspase inhibition prevented GRP78 RNAi-mediated therapy resensitization. Furthermore, knockdown of GRP78 and beclin 1 (BECN1) synergistically restores antiestrogen sensitivity in resistant cells. The use of GRP78 to integrate the cellular functions of apoptosis and autophagy to control cell fate raises the provocative question that this signaling may be widely applicable and represent a major stress response that explains how many different cell types could respond to stressors and acquire resistance to therapeutic interventions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4995. doi:1538-7445.AM2012-4995