bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2915: The oxidation state of DJ-1 determines the cell fate during oxidative stress triggered by Fenretinide (4-HPR): autophagy or apoptosis.
Authors: Cao Ji , Ying Meidan , Xie Nan , Zhang Jun , Liu Xiaowen , He Qiaojun , Yang Bo 
Published: August 2014

Abstract
Increasing oxidative stress caused by many anti-cancer drugs is commonly accompanied with a switch from autophagy, a cyto-protective response, to apoptosis in cancer cells. However, the underlying mechanism of this process is still poorly understood. To address this we chose fenretinide (4-HPR) as the candidate drug since the major anti-cancer mechanism of this drug is reactive oxygen species (ROS) induction. We have shown previously and herein that 4-HPR-driven ROS induce the autophagy-apoptosis transition in a threshold manner in vitro and vivo. During this process, ASK1-regulated JNK1 or p38 signaling is response for 4-HPR-induced autophagy or apoptosis, respectively. Given ASK1 play a pivotal role in the selective activation of individual signaling, we further characterize the potential regulating unit of ASK1 by immunoprecipitation following LC/MS/MS analysis. Of note, DJ-1, a crucial antioxidant protein, is identified from a total of 7 fragments. We show that DJ-1 interacts with ASK-1 under moderate oxidative stress, but segregate from ASK-1 under lethal level of oxidative stress, suggesting DJ-1 may be a potent key regulator of autophagy-apoptosis transition. Interestingly, various oxidation statuses and the stability of homo-dimer formation of DJ-1 are highly related to different levels of intracellular oxidative stress. Moreover, we apply two kinds of artificial DJ-1 mutants at position C106 or E18 and further confirm that DJ-1 served as an oxidative sensor to determine the switch between autophagy and apoptosis triggered by 4-HPR. Hence, different oxidation state of DJ-1 modulates ASK-1-JNK1/p38 signaling activation to dictate the cellular response to oxidative stress: to autophagy or apoptosis.
Citation Format: Ji Cao, Meidan Ying, Nan Xie, Jun Zhang, Xiaowen Liu, Qiaojun He, Bo Yang. The oxidation state of DJ-1 determines the cell fate during oxidative stress triggered by Fenretinide (4-HPR): autophagy or apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2915. doi:10.1158/1538-7445.AM2013-2915
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 292: Breast cancer malignancy is regulated by PAX5 through the disruption of FAK1 signaling.
Authors: Benzina Sami , O'Brien Pierre , Guerrette Roxann , Robichaud Gilles 
Published: August 2014

Abstract
Breast cancer is the most common cancer diagnosed in women worldwide. 30% of these women will succumb to their disease. More specifically, metastasis accounts for 90% of deaths in breast cancers patients. Therefore, the study of genetic factors regulating cancer malignancy is a top priority to mitigate the morbidity and mortality associated to this disease. PAX5 (Paired Box 5) is a transcriptional factor normally implicated in embryogenesis and B cell differentiation. However, the aberrant expression of PAX5 is associated to several types of cancer pathology and more recently in breast cancer.
We have recently reported that PAX5 promotes epithelialisation and its expression inversely correlates with the Focal Adhesion Kinase 1 (FAK1), a key component in cancer motility and invasion leading to metastasis. On one hand, these finding suggest that PAX5 could attenuate FAK-mediated epithelial-mesenchymal transitioning (EMT) of primary tumors. On the other hand, PAX5 could also initiate the mesenchymal-epithelial transitioning (MET) of circulating cancer cells enabling them to colonize and establish secondary tumours.
In this study we set out to validate the role of PAX5 in the metastatic cascade of mammary tumours, particularly to uncover the molecular regulation of FAK1 cascades through PAX5 in breast cancer cell malignancy. Through conditional expression of the PAX5 gene in breast cancer cells, we demonstrate experimentally a negative regulation of FAK1 protein and phosphorylation levels mediated by PAX5 over expression. We also confirm that PAX5 suppresses the transcriptional expression of FAK1. Further investigation shows a PAX5-mediated suppression of FAK1 signaling pathways (e.i. AKT, p38, JNK and Paxillin) leading to attenuated cancer cell proliferation, death and migration processes. These findings bring light to molecular mechanisms driving breast cancer malignancy and benefit our quest in the development of diagnostic and therapeutic strategies.
Citation Format: Sami Benzina, Pierre O'Brien, Roxann Guerrette, Gilles Robichaud. Breast cancer malignancy is regulated by PAX5 through the disruption of FAK1 signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 292. doi:10.1158/1538-7445.AM2013-292
Abstract 2921: NAD(P)H quinone oxidoreductase 1 regulates pro-inflammatory mediators associated with prostate tumorigenesis.
Authors: Thapa Dinesh , Kumar Addanki P. , Ghosh Rita 
Published: August 2014

Abstract
Oxidative stress and inflammation are both important in the neoplastic transformation of the prostate. NAD(P)H Quinone Oxidoreductase 1 (NQO1) is a key antioxidant enzyme that protects against quinone-derived reactive intermediates and maintains a cellular pool of antioxidants. Various studies conducted using NQO1 knockout mice suggested its potential role in carcinogenesis. However the role of NQO1 has not been fully explored in prostate cancer. Here we show that NQO1 silencing by a specific shRNA (shNQO1) increased cell survival, proliferation, colony formation, migration and hormone-independent survival in hormone-responsive human prostate cancer cells LNCaP. Genome wide array revealed that NQO1 blockade significantly upregulated pro-inflammatory mediators (e.g., IL-32, CCL2, IL-8, IL-17C, IL-10RA, CXCR2, CXCR7, NOS3) associated with prostate tumorigenesis. Cytokine profiling further confirmed the increased IL-8 production in conditioned-media from NQO1 knockdown cells compared to the parental cells. However, enforced expression of NQO1 in these cells did not alter IL-8 and other inflammatory mediators. Our data indicate that inflammatory mediators produced by NQO1 knockdown LNCaP cells may be responsible for the hormone-independent survival. Since these inflammatory mediators influence prostate cancer development and castration resistance, strategies modulating cellular antioxidants to regulate NQO1 and other important players in NQO1-signaling may provide multifaceted opportunities for prostate cancer prevention. Supported by a postdoctoral fellowship from CPRIT (DT) and RO1 CA 149516 (RG).
Citation Format: Dinesh Thapa, Addanki P. Kumar, Rita Ghosh. NAD(P)H quinone oxidoreductase 1 regulates pro-inflammatory mediators associated with prostate tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2921. doi:10.1158/1538-7445.AM2013-2921
Abstract 2922: Stoichiometric depletion of glutathione by anticancer agent JS-K.
Authors: Holland Ryan J. , Maciag Anna E. , Cheng Robert Y.-S. , Rodriguez Luis G. , Saavedra Joseph E. , Anderson Lucy M. , Keefer Larry K. 
Published: August 2014

Abstract
JS-K is a nitric oxide (NO)-releasing drug of the O2-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models. It is activated for NO release by reaction with glutathione (GSH), a step that consumes an equivalent of GSH, effectively irreversibly. The two equivalents of NO thus released can be oxidized intracellularly, leading to S-nitrosylation and S-glutathionylation of GSH in a cascade of further reactions that consume additional equivalents of GSH and generate GSH disulfide (GSSG). The GSH/GSSG redox couple is the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. Here we show that depletion of GSH on treating U937 leukemia cells with JS-K markedly raises the reduction potential of the cell, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. The data indicate that multiplicative depletion of reduced GSH and deregulation of intracellular redox balance are important steps in the mechanism of JS-K's cytotoxic action.
An additional GSH-consuming pathway was found to occur with Double JS-K, an aryl bis(diazeniumdiolate) created with the purpose of doubling the payload of NO. Double JS-K caused pronounced protein glutathionylation, in contrast to its monovalent counterpart. Serving as a bivalent electrophile, Double JS-K irreversibly crosslinked GSH to protein thiols through its aromatic linker. The results provide a previously unrecognized component of the multifaceted mechanism of action of bivalent electrophiles of the arylated diazeniumdiolate class.
Citation Format: Ryan J. Holland, Anna E. Maciag, Robert Y.-S. Cheng, Luis G. Rodriguez, Joseph E. Saavedra, Lucy M. Anderson, Larry K. Keefer. Stoichiometric depletion of glutathione by anticancer agent JS-K. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2922. doi:10.1158/1538-7445.AM2013-2922
Abstract 2924: The role of autophagy in telomere damage-induced replicative senescence.
Authors: Charles Florie , Debnath Jayanta , Stohr Bradley 
Published: August 2014

Abstract
Recent studies have implicated autophagy in multiple aspects of cancer biology, including oncogene-induced senescence (OIS) and genome instability. Autophagy is thought to control the transition to OIS through its ability to regulate the Senescence Associated Secretory Phenotype (SASP), which is necessary and sufficient for OIS. In addition, autophagy can suppress genome instability by limiting p62 accumulation in an apoptosis-deficient setting. In this study, we explored the role of autophagy in replicative senescence, an important barrier to tumorigenesis that is driven by telomere dysfunction and that is very distinct from OIS. We modeled replicative senescence by expressing mutant telomerase in human diploid fibroblasts, which rapidly induces telomere dysfunction and senescence. We observed strong induction of autophagic flux in response to telomere dysfunction prior to and during senescence. To determine the role of autophagy in the cellular response to telomere damage, we examined multiple components of the dysfunctional telomere response: transition and maintenance of senescence, SASP, DNA damage response, genome instability, and heterochromatin foci. In cells depleted of key autophagy mediators (ATGs), we did not observe a clear defect in the transition to senescence, as was previously seen with OIS. However, we did observe an outgrowth population of non-senescent cells among the senescent autophagy-deficient population, suggesting a possible defect in the maintenance of senescence. We also found that telomere dysfunction induced secretion of IL6 in an autophagy-dependent manner. Lastly, we observed an increase in polyploid cells in Atg7-deficient checkpoint-proficient cells, suggesting a role for autophagy in maintaining genome stability during the dysfunctional telomere response. Our results suggest that autophagy controls several aspects of the cellular response to telomere dysfunction in normal human cells.
Citation Format: Florie Charles, Jayanta Debnath, Bradley Stohr. The role of autophagy in telomere damage-induced replicative senescence. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2924. doi:10.1158/1538-7445.AM2013-2924
Abstract 2928: Interleukin-1 receptor-associated kinase-2 (IRAK2) is a critical mediator of endoplasmic reticulum (ER) stress.
Authors: Palaniyandi Ravanan , Benosman Samir , Hou Ying-Chen , Correa Ricardo G. , Yu Minjia , Gulen Muhammet Fatih , Li Xiaoxia , Thomas James , Matsuzawa Yasuko , Matsuzawa Shu-Ichi , Reed John C. 
Published: August 2014

Abstract
Endoplasmic reticulum (ER) stress occurs when unfolded proteins accumulate in the lumen of the organelle, triggering signal transduction events that contribute either to cellular adaptation and recovery or alternatively to cellular dysfunction and death. ER stress has been implicated in numerous diseases, including cancer where harsh tumor microenvironments induce ER stress and create pressure for evolution of malignant clones that have acquired mechanisms for successful adaptation to stressful environments. To identify novel modulators of ER stress, we undertook a siRNA library screen of the kinome, revealing Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) as a contributor to unfolded protein response (UPR) signaling and ER stress-induced cell death. Knocking down expression of IRAK2 (but not IRAK1) in cultured mammalian cells suppresses ER stress-induced expression of the pro-apoptotic transcription factor CHOP and activation of stress kinases. Similarly, RNAi-mediated silencing of the IRAK family member Tube (but not Pelle) suppresses activation of stress kinase signaling induced by ER stress in Drosophila cells. The action of IRAK2 maps to the IRE1 pathway, rather than the PERK or ATF6 components of the UPR. Interestingly, ER stress also induces IRAK2 gene expression in an IRE1/XBP1-dependent manner, suggesting a mutually supporting amplification loop involving IRAK2 and IRE1. In vivo, ER stress induces Irak2 expression in mice. Moreover, Irak2 gene knockout mice display defects in ER stress-induced CHOP expression and IRE1 pathway signaling. These findings demonstrate an unexpected linkage of the innate immunity machinery to UPR signaling, revealing IRAK2 as a novel amplifier of the IRE1 pathway involved in ER stress signaling. Future analysis of the role of IRAK2 in animal models of cancer will aid in assessing whether IRAK2 provides a novel targets for potential cancer therapeutics development.
(Supported by NIH grant AG-15393).
Citation Format: Ravanan Palaniyandi, Samir Benosman, Ying-Chen Hou, Ricardo G. Correa, Minjia Yu, Muhammet Fatih Gulen, Xiaoxia Li, James Thomas, Yasuko Matsuzawa, Shu-Ichi Matsuzawa, John C. Reed. Interleukin-1 receptor-associated kinase-2 (IRAK2) is a critical mediator of endoplasmic reticulum (ER) stress. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2928. doi:10.1158/1538-7445.AM2013-2928
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 293: TGF-b regulates Par-4 expression through XIAP in ovarian and endometrial cancers.
Authors: Fabi Francois , Parent Sophie , Leblanc Valérie , Asselin Eric 
Published: August 2014

Abstract
The lethality of gynecological malignancies can be explained by their propensity to develop chemioresistance and metastases. The loss of apoptotic pathways is one of the major underlying mechanisms by which tumors become resistant to treatments. This loss can be explained by the silencing of pro-apoptotic proteins that would normally contrive the cell into suicide. Par-4 is a tumor suppresor protein that is widely expressed but only functionally silenced in most endometrial cancer. This protein presents the unique ability to induce apoptosis selectively in cancer cells. We have recently demonstrated that Par-4 is a substrate of caspase-3 and the resulting cleaved fragment retains its apoptotic-inducing capabilities. We have also evidenced that TGF-β, a known instigator of EMT, regulates the invasiveness of endometrial cancer cells and Par-4 expression. TGF-β has also been shown to increase the expression of XIAP, an important promoter of cell survival and invasiveness in endometrial cancer. In this study, we have investigated the effect of TGF-ß and XIAP on Par-4 expression in ovarian and endometrial cancer.
We have performed rescue experiment in which MEFs cells from XIAP KO mice were cultured and transfected with either an empty plasmid, a wild-type XIAP plasmid or a XIAP mutated RING domain plasmid. We have then submitted these cells to cisplatin treatment. In the empty vector transfectants, we have found that the absence of XIAP results in Par-4 cleavage, increased cleaved caspase-3 and cleaved PARP. The rescue of XIAP inhibited the apoptotic machinery and Par-4 cleavage thus resulting in increased chemoresistance. This effect was reversed using the mutated XIAP plasmid. We have also treated endometrial cancer cells (HeLa, KLE) with TGF-ß3 and observed an higher expression of EMT markers such as Snail, Vimentin and N-Cadherin; Par-4 was also upregulated by TGF-ß3. Finally, we have overexpressed ovarian A2780 cancer cells with Par-4 plasmid, which resulted in the upregulation of Snail and Vimentin. We confirmed these results using Par-4 siRNA and found that Snail and Vimentin expression were reduced.
Altogether, results of the present study shed new light in the underlying mechanisms of Par-4 regulation and apoptosis induction. The assembled data also suggests that TGF-β plays a cardinal role in the regulation of Par-4 expression, which regulates EMT in gynecological cancers.
Citation Format: Francois Fabi, Sophie Parent, Valérie Leblanc, Eric Asselin. TGF-b regulates Par-4 expression through XIAP in ovarian and endometrial cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 293. doi:10.1158/1538-7445.AM2013-293
Abstract 2938: Altered caspase-8 protein expression and activity in TRAIL-resistant normal human fibroblasts.
Authors: Crowder Roslyn N. , Dicker David T. , El-Deiry Wafik S. 
Published: August 2014

Abstract
TNF-related apoptosis-inducing ligand (TRAIL)-mediated cell death is currently being utilized in newly developed cancer therapies. The molecular basis of normal cell resistance to TRAIL-mediated apoptosis, and thus therapeutic index, remains largely unexplored. We investigated TRAIL sensitivity in normal fibroblasts (HFF, WI-38, MRC-5) and found that normal fibroblasts have decreased protein expression of initiator caspase-8 that is required for complete TRAIL signaling. TRAIL treatment caused caspase-8 cleavage in TRAIL-sensitive cancer cells. Yet, no caspase-8 cleavage was observed in normal fibroblasts after TRAIL treatment. TRAIL treated fibroblasts had modest increase in caspase-8 activity compared to TRAIL-susceptible cancer cells.
Previous studies have found caspase-8 polyubiquitination necessary for caspase-8 aggregation and complete activation. Additionally, reports show deubiquitination of caspase-8 limits caspase-8 activity. Therefore, we examined caspase-8 ubiquitination in normal fibroblasts. Caspase-8 ubiquitination, analyzed by Western blotting, in normal fibroblasts was found to be decreased compared to TRAIL-sensitive cancer cells. TRAIL sensitivity in normal fibroblasts after treatment with deubiquitinase inhibitor PR-619 was also assessed. Normal fibroblasts had markedly decreased cell viability after co-treatment with TRAIL and PR-619 compared to TRAIL-only treated fibroblasts. Cancer cell viability after co-treatment with TRAIL and PR-619 was similar to cancer cells merely treated with TRAIL. Normal fibroblasts co-treated with TRAIL and PR-619 had increased caspase-8 cleavage, PARP cleavage, and caspase-8 activity. The increased cell death seen in normal fibroblasts with TRAIL and PR-619 co-treatment was greatly inhibited when caspase inhibitor ZVAD was added, demonstrating the cell death with TRAIL and PR-619 was caspase-mediated. Our data suggest that caspase-8 deubiquitination may be a contributing factor in normal fibroblast resistance to TRAIL-mediated apoptosis. Our current studies are focused on investigating the role of deubiquitinase A20, previously found to deubiquitinate caspase-8, in normal fibroblast caspase-8 deubiquitination.
Citation Format: Roslyn N. Crowder, David T. Dicker, Wafik S. El-Deiry. Altered caspase-8 protein expression and activity in TRAIL-resistant normal human fibroblasts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2938. doi:10.1158/1538-7445.AM2013-2938
Abstract 2941: The role of lysine acetylation in the tumor cell response to stress.
Authors: Heppler Lisa , Andersen Joshua L. 
Published: August 2014

Abstract
Solid breast tumors contain heterogenous microenvironments where tumor cells are often exposed to metabolic stress (e.g., hypoxia due to poor blood supply). Such environments select for tumor cells that can adapt metabolically to survive, while other cells fail to adapt and undergo cell death. The survival of cells through periods of hypoxia can promote chemoresistance and metastasis (1). Thus, it is critical that we develop therapeutic strategies to enhance metabolic-stress-induced tumor cell death. One promising strategy is the modulation of lysine acetylation pathways by HDAC inhibitors that potently promote cell death in response to various stimuli, including hypoxia/glucose withdrawal. Given the relatively non-specific nature of chemical HDAC inhibitors, the precise acetylation-regulating enzymes and pathways that govern cell death in these settings have yet to be fully elucidated. Our goal is to identify the cellular factors that link acetylation to cell death in response to hypoxia and other metabolic stresses, with the hope that such factors could be exploited therapeutically in cancer.
Previous studies have implicated protein lysine acetylation in the coordination of cellular metabolism to the available nutrient supply (2). In line with this idea, our preliminary data suggest that lysine acetylation pathways dictate whether breast tumor cells survive (through metabolic adaptation) or die in response to hypoxia and glucose deprivation. Moreover, we have observed that general increases in protein lysine acetylation precede the activation of pro-apoptotic caspases in response to these stresses. In addition, our proteomics efforts have shown that breast tumors that are sensitive to hypoxia/glucose withdrawal exhibit significant increases in acetylation across the proteome, whereas resistant cells show very little change. Together, our data suggest that lysine acetylation pathways play a role in metabolic adaption and survival under conditions of hypoxia/glucose withdrawal. We are currently using an RNAi approach to target all known deacetylases, acetyl-transferases, and metabolic enzymes that modulate acetylation (e.g., acetyl-CoA synthetase) in order to identify the specific acetylation-regulating factors that govern tumor cell susceptibility to metabolic stress.
Citation Format: Lisa Heppler, Joshua L. Andersen. The role of lysine acetylation in the tumor cell response to stress. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2941. doi:10.1158/1538-7445.AM2013-2941