bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2263: Change in miRNA by suberoylanilide hydroxamic acid affects lung cancer cell death via regulating thioredoxin
Authors: You Bo R. , Han Bo Ram , Park Woo Hyun 
Published: May 2015

Abstract
Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor to have the anti-tumor effect. Here, we evaluated the anti-growth effect of SAHA on lung cancer (A549, SK-LU-1, HCC-95, HCC-1588, NCI-H460, NCI-H1299, Calu-6, HCC-33, NCI-H69) and normal lung (human small airway epithelial cells and human pulmonary fibroblast) cells in relation to reactive oxygen species (ROS) and thioredoxin (Trx) levels. SAHA inhibited the growth of lung cancer cells, and induced a G2/M phase arrest and apoptotic cell death in these cancer cells. In contrast, SAHA did not significantly inhibit the growth of normal lung cells and induce apoptotic cell death. Concerning the oxidative stress, SAHA increased ROS levels in lung cancer cells and induced glutathione (GSH) depletion. Moreover, it decreased the expression level of Trx1 in lung cancer cells. While the overexpression of Trx1 attenuated death and GSH depletion in SAHA-treated lung cancer cells, the downregulation of Trx1 intensified those in these cells. In addition, SAHA increased miR-629 level in lung cancer cells. The mRNA level of Trx1 was decreased by SAHA. Furthermore, the 3′ UTR region of Trx1 was regulated by miR-629. In conclusion, SAHA inhibited the growth of lung cancer cells via cell cycle arrest and apoptosis. The growth inhibition was related to the levels of Trx1 and miR-629. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2008-0062279) and supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, (2013006279).
Citation Format: Bo Ra You, Bo Ram Han, Woo Hyun Park. Change in miRNA by suberoylanilide hydroxamic acid affects lung cancer cell death via regulating thioredoxin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2263. doi:10.1158/1538-7445.AM2014-2263
Abstract 2266: Investigating the role of the anti-apoptotic protein ARC in breast cancer cell DNA repair
Authors: Grunblatt Eli , Madan Evanka , Roy Sweta , Goswami Sumanta 
Published: May 2015

Abstract
According to the American Cancer Society, more than 90% of breast cancer patients who succumb to the condition die as a result of the cancer metastasizing to other areas of the body. Our lab has previously shown that the presence of a chemoresistant invasive subpopulation of breast carcinoma cells is correlated with the prevalence of metastasis. Additionally, we have hypothesized that chemoresistance and survival of these cancer cells which eventually leads to relapse and metastasis following initial treatment with chemotherapeutic agents is achieved by enhanced DNA repair capability in this population. We reported that an anti-apoptotic protein ARC (apoptosis repressor with caspase recruitment domain) is over expressed in the invasive mammary cancer cells that are resistant to standard chemotherapeutic agents. Further, we have shown that ARC over expressing cells are resistant to chemotherapy both in vivo and in vitro. In this study, we examined cellular DNA repair signaling pathways in order to delineate the role of ARC in the pathogenesis of breast cancer. Utilizing cell lines where ARC was either knocked down or overexpressed, we investigated potential correlations of ARC with DNA repair capability by means of the single cell gel electrophoresis assay (comet assay). The results of these experiments indicated that over expression of ARC leads to increased cellular DNA repair while knocking it down leads to decreased cellular DNA repair.
In order to determine the molecular basis of the role of ARC in the DNA repair pathways, we have performed qRT-PCR based gene expression analysis on ARC modified cell lines using techniques previously established in our lab. The results of these experiments indicated that increased levels of ARC are correlated with upregulation of key genes in single stranded DNA repair pathways such as the base excision and nucleotide excision repair pathways. We are working to identify the specific domain of ARC that serves as its effector in the DNA repair pathways. In particular, we are looking at the caspase recruitment domain (CARD) of ARC which is known to be key for ARC`s function in the apoptotic pathways. Once this domain is identified, it may serve as a potential drug target, the silencing of which could result in the disruption of key pathways required for invasive breast cancer cell survival. Such therapy may facilitate the ablation of chemoresistant breast cancer cell populations, prevent metastasis and tumor relapse, and increase long term patient survival.
Citation Format: Eli Grunblatt, Evanka Madan, Sweta Roy, Sumanta Goswami. Investigating the role of the anti-apoptotic protein ARC in breast cancer cell DNA repair. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2266. doi:10.1158/1538-7445.AM2014-2266
Abstract 2268: Augmentation of DR5 expression by calmodulin antagonists sensitizes TRA-8-induced apoptosis in pancreatic cancer
Authors: Yuan Kaiyu , Zhou Tong , McDonald Jay , Chen Yabing 
Published: May 2015

Abstract
Pancreatic cancer is the fourth leading cause of cancer death in the USA. The 5-year survival rate has only improved from 2% to 6% in the past 35 years. TNF-related apoptosis-inducing ligand (TRAIL) or agonistic antibodies bind to death receptor 4 or 5 and induce apoptosis in a wide variety of tumors. TRA-8, a humanized activating antibody for the death receptor 5 (DR5), is a potent apoptosis-inducing reagent for cancer cells. However, several pancreatic cell lines are resistant to TRA-8-induced apoptosis. The goal of our studies is to indentify therapeutic agents that sensitize resistant pancreatic cancer cells to TRA-8-induced apoptosis and determine the underlying mechanism.
Among an array of compounds, we identified that trifluoperazine (TFP) and tamoxifen (TMX), two calmodulin (CaM) antagonists, enhanced TRA-8-induced cell death of TRA-8 resistance pancreatic cells. Both TFP and TMX increased TRA-8-induced apoptosis of resistant PANC-1 cells in dose-dependent manners. TMX treatment enhanced the efficacy of TRA-8 therapy on tumorigenesis of PANC-1 cells in a mouse xenograft model by 5 fold (n=7, p&lt;0.05). We found that the effects of CaM antagonists on TRA-8-induced apoptosis were mediated by its induction of caspase-8 activation, as TMX increased TRA-8-induced activation of caspase-8 in the DR5-recruited signaling complex whereas caspase-8 inhibition by Z-IETD-FMK markedly decreased TRA-8-induced apoptosis as well as activation of downstream apoptosis effector caspase-3. Analysis of the expression of the death receptors revealed that TFP and TMX increased the expression of the DR5, at both mRNA and protein levels. Furthermore, TFP and TMX increased acetylation of histone H3 and H4, which may contribute their augmentation of DR5 expression. In summary, we have demonstrated that CaM antagonists increase DR5 expression and DR5-mediated caspase-8 activation, thus sensitizing pancreatic cancer to TRA 8-induced apoptosis. Our results identify an important role for CaM in regulating of DR5-mediated apoptosis signals in pancreatic cancer cells and support the possible use of combined TRA-8 and CaM antagonists to treat pancreatic cancer.
Citation Format: Kaiyu Yuan, Tong Zhou, Jay McDonald, Yabing Chen. Augmentation of DR5 expression by calmodulin antagonists sensitizes TRA-8-induced apoptosis in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2268. doi:10.1158/1538-7445.AM2014-2268
Abstract 227: Estrogen receptor-α and tumor initiating cells are novel targets of diallyl trisulfide in breast cancer cells
Authors: Hahm Eun-Ryeong , Kim Su-Hyeong , Singh Shivendra V. 
Published: May 2015

Abstract
Epidemiological studies suggest a protective role for Allium vegetables, such as garlic, against breast and other cancers. Diallyl trisulfide (DATS) is a promising oil-soluble anticancer metabolite generated after cutting or chewing of Allium vegetables. We have shown previously that DATS inhibits viability of human breast cancer cells (MCF-7 and MDA-MB-231) and a cell line derived from spontaneously developed tumor of a mouse mammary tumor virus-neu mouse by causing apoptosis induction. We also found that a non-tumorigenic normal human mammary epithelial cell line (MCF-10A) is resistant to cell death induction by DATS. Studies by others have demonstrated in vivo efficacy of DATS against MCF-7 xenografts in nude mice. The present study builds upon these observations and identifies novel targets of DATS in breast cancer cells. MCF-7 and T47D cells exposed to DATS exhibited downregulation of estrogen receptor-α (ER-α) protein, which peaked between 12 and 24 h post-treatment. Diallyl sulfide and diallyl disulfide analogs were relatively less effective in suppressing protein level of ER-α compared with DATS. The 17β-estradiol (E2)-induced expression of pS2, an ER-α target gene product, was also decreased in the presence of DATS. Downregulation of ER-α protein expression resulting from DATS treatment was accompanied by a decrease in nuclear level of ER-α, suppression of ER-α mRNA, and inhibition of ERE2e1b-luciferase reporter activity. Moreover, apoptotic cell death induced by DATS was partially but statistically significantly attenuated in the presence of E2 in MCF-7 cells as well as by overexpression of ER-α in MDA-MB-231 cells. DATS treatment inhibited breast cancer stem cell (bCSC) population as evidenced by flow cytometric analysis of CD44high/CD24low/epithelial specific antigen positive population, aldehyde dehydrogenase 1 activity, and mammosphere frequency in MCF-7 and SUM159 cells. Inhibition of bCSC by treatment with DATS was associated with downregulation of EZH2 and Kruppel-like factor 4 proteins in both MCF-7 and SUM159 cells. In conclusion, the present study identifies ER-α and bCSC as novel targets of DATS in mammary cancer cells. This study was supported by the grant RO1 CA113363-09 awarded by the National Cancer Institute.
Citation Format: Eun-Ryeong Hahm, Su-Hyeong Kim, Shivendra V. Singh. Estrogen receptor-α and tumor initiating cells are novel targets of diallyl trisulfide in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 227. doi:10.1158/1538-7445.AM2014-227
Abstract 2271: Effective therapy for advanced renal cell carcinoma using triptolide and TRAIL receptor agonists
Authors: Griffith Thomas S. , Brincks Erik L. , Kucaba Tamara A. , James Britnie R. , Sangwan Veena , Banerjee Sulagna , Saluja Ashok 
Published: May 2015

Abstract
Metastatic renal cell carcinoma (RCC) is incurable. IFNα or IL-2 immunotherapy has been used for RCC for more than 20 years, but response rates remain low and these cytokines can generate toxic. More recently, administration of multikinase inhibitors or anti-VEGF receptor mAb has become popular, but these agents are largely palliative and tumor regression is common. The shortcomings in current therapeutic options for patients with metastatic RCC provide the rationale for the development of novel treatment protocols. Triptolide, a diterpene triepoxide from the medicinal herb Tripterygium wilfordii, can suppress cell growth and induce apoptosis in a range of human tumor cells. Further, triptolide also sensitizes tumor cells to TNF-related apoptosis-inducing ligand (TRAIL). The objective of this study was to determine the effectiveness of combining triptolide with TRAIL receptor agonists against RCC. In vitro, the combination of triptolide and recombinant human TRAIL protein decreased cell viability in the human RCC cell line ACHN cells compared with either treatment alone. This decrease in viability correlated with increased induction of apoptosis (positive Annexin V staining) and caspase activation. The triptolide-induced sensitization was accompanied by decreased HSP70, HSP27, and HSF1 expression, as well as increased surface expression of TRAIL-R2. Similar in vitro treatment of the mouse renal cell adenocarcinoma cell line, Renca, demonstrated that triptolide enhanced the killing of these cells by membrane-bound TRAIL or agonistic anti-DR5 mAb. In vivo treatment of mice bearing orthotopic and metastatic Renca tumors showed that combination therapy consisting of minnelide (a water soluble version of triptolide) and agonistic anti-DR5 mAb resulted in significantly decreased tumor burden and increased animal survival compared to either therapy alone. Collectively, our data suggest that triptolide sensitizes RCC cells to TRAIL-induced apoptosis, which is accompanied by decreased heat shock protein expression and altered TRAIL receptor expression. These data also suggest that the combination of TRAIL receptor agonists and triptolide may prove to be an effective treatment for metastatic RCC, especially at doses that show suboptimal tumoricidal activity when used individually.
Citation Format: Thomas S. Griffith, Erik L. Brincks, Tamara A. Kucaba, Britnie R. James, Veena Sangwan, Sulagna Banerjee, Ashok Saluja. Effective therapy for advanced renal cell carcinoma using triptolide and TRAIL receptor agonists. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2271. doi:10.1158/1538-7445.AM2014-2271
Abstract 2273: c-Rel is a critical mediator of NF-κB-dependent apoptosis resistance of pancreatic cancer cells against TRAIL
Authors: Geismann Claudia , Grohmann Frauke , Wirths Gabriele , Sebens Susanne , Dreher Anita , Häsler Robert , Zeissig Sebastian , Schreiber Stefan , Rosenstiel Philip , Schäfer Heiner , Arlt Alexander 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of six months despite palliative radio-chemotherapy. The transcription factor NF-κB has been shown to be a critical component of dysregulated transcription factor activity conferring this profound resistance against chemotherapeutic drugs and death receptor induced apoptosis. Despite extensive data on the role of the most abundant NF-κB subunit p65/RelA in PDAC apoptosis control, only little knowledge of the role of the subunit c-Rel in solid cancers exists. In the present study, three pancreatic carcinoma cell lines (Panc1, Patu8988t, MiaPaca2) were analysed for the role of c-Rel in resistance against TRAIL induced apoptosis. TRAIL resistant Panc1 and Patu8988 cells exhibit a strong TRAIL inducible NF-κB activity, whereas TRAIL sensitive MiaPaca2 cells displayed only a small increase in NF-κB binding activity. Transfection with siRNA against the c-Rel subunit of NF-κB sensitized the TRAIL resistant cells in a comparable fashion like siRNA targeting the p65/RelA subunit. Gel shift analysis revealed that together with the p65/RelA subunit, c-Rel is part of the TRAIL inducible NF-κB complex in PDAC. Array analysis results suggested NFATc2 as a c-Rel target gene that is one of the 15 strongest TRAIL inducible genes in apoptosis-resistant Panc1 cells. siRNA targeting c-Rel strongly reduced TRAIL induced NFATc2 activity in TRAIL resistant PDAC cells. Furthermore siRNA targeting NFATc2 sensitized these PDAC cells against TRAIL induced apoptosis. Finally, TRAIL induced expression of COX-2 was strongly reduced through siRNA targeting c-Rel or NFATc2 and pharmacological inhibition of COX-2 with celecoxib strongly increased TRAIL apoptosis.
In conclusion, c-Rel is a critical mediator of NF-κB dependent anti-apoptotic signalling in PDAC through activation of NFATc2 and COX-2.
Citation Format: Claudia Geismann, Frauke Grohmann, Gabriele Wirths, Susanne Sebens, Anita Dreher, Robert Häsler, Sebastian Zeissig, Stefan Schreiber, Philip Rosenstiel, Heiner Schäfer, Alexander Arlt. c-Rel is a critical mediator of NF-κB-dependent apoptosis resistance of pancreatic cancer cells against TRAIL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2273. doi:10.1158/1538-7445.AM2014-2273
Abstract 2279: Adenine nucleotide translocase-2 is a key molecule in the enhancement of TRAIL sensitivity by flavonoids
Authors: Oishi Masakatsu , Iizumi Yosuke , Ueda Takashi , Ito Saya , Nakamura Terukazu , Hongo Fumiya , Naya Yoshio , Miki Tsuneharu , Sakai Toshiyuki 
Published: May 2015

Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine which belongs to the tumor necrosis factor family. TRAIL binds to death receptor (DR) 4 and DR5 and selectively induces apoptosis in various malignant tumors, but not in normal cells. Therefore, TRAIL is an attractive cancer therapeutic agent. However, several malignant tumors have resistance to TRAIL and overcoming this resistance is essential for chemotherapy using the TRAIL pathway. Anticancer agents such as bortezomib, etoposide, doxorubicin, and irinotecan have been reported to upregulate DR5 and sensitize cancer cells to TRAIL in vitro and in vivo. Since these agents cause various adverse effects, we and others have screened dietary compounds inducing DR5 expression and identified several flavonoids as DR5 inducers. For instance, dietary flavonoid apigenin and quercetin enhance TRAIL sensitivity by upregulating DR5. However, the mechanisms by which these flavonoids upregulate DR5 are unknown. To elucidate the mechanisms by which these flavonoids induce DR5, we explored the proteins binding to apigenin and quercetin, but not the flavonoid genistein which did not induce DR5. We used magnetic FG beads, which recently revealed the target of thalidomide and the mechanism of thalidomide teratogenicity. We identified ANT2 as a binding protein of flavonoids, apigenin and quercetin, upregulating DR5. As with the treatment of apigenin and quercetin, knockdown of ANT2 enhanced TRAIL-induced apoptosis by upregulating DR5. Moreover, knockdown of ANT2 attenuated the enhancement of TRAIL-mediated apoptosis by apigenin and quercetin. In the present study, we show that ANT2 is a target of flavonoids which upregulate DR5 and sensitize malignant tumor cells to TRAIL.
Citation Format: Masakatsu Oishi, Yosuke Iizumi, Takashi Ueda, Saya Ito, Terukazu Nakamura, Fumiya Hongo, Yoshio Naya, Tsuneharu Miki, Toshiyuki Sakai. Adenine nucleotide translocase-2 is a key molecule in the enhancement of TRAIL sensitivity by flavonoids. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2279. doi:10.1158/1538-7445.AM2014-2279
Abstract 2281: Molecular mechanisms by which cFLIP overexpression regulates TRAIL-induced NF-κB activation and lymphoma survival
Authors: Habelhah Hasem , Workman Lauren , Zhang Laiqun 
Published: May 2015

Abstract
Although recombinant TRAIL and agonistic antibodies directed against TRAILR1/2 are considered potential anti-cancer agents, their anti-cancer response in clinical trials was poor with the vast majority of patients showing no remission. In addition, TRAIL has been found to act as tumor promoters in certain contexts, increasing metastasis in apoptosis-resistant cancer cells by activating NF-κB. Therefore, defining the mechanism that permits TRAIL to activate NF-κB is critical for the development of strategies that maximize the potential effectiveness of TRAIL in clinical applications. We found that cFLIP-mediated and caspase-8-dependent cleavage of RIP1 at two sites, D180 in the kinase domain (KD) and D324 in the intermediate domain (ID), determines the activation state of the IKK/NF-κB pathway in response to TRAIL treatment. In apoptosis sensitive cells, caspase-8 cleaves RIP1 at KD and ID domains immediately after its recruitment to the receptor complex, impairing IKK recruitment and activation. In cFLIP-overexpressing cells, cFLIP restricts caspase-8 activity and RIP1 cleavage, generating a KD-cleaved RIP1 fragment that is capable of activating the NF-κB but not the apoptotic pathway. Of note, cFLIP expression, caspase-8 activity and RIP1 cleavage in KD per se are not directly involved in IKK activation; instead, they suppress RIP1-dependent activation of the apoptotic and necrotic cascades, and thereby ensure the integrity of the NF-κB pathway. Moreover, inflammatory ligands such as CD40L deplete cytoplasmic pool of TRAF2 and cIAP1/2, and promote RIP1 cleavage in lymphomas. Inhibition of RIP1 cleavage in KD suppresses NF-κB activation, and significantly increases TRAIL-induced cell death even in cFLIP-overexpressing lymphomas. Importantly, a portion of RIP1 is constitutively cleaved in many types of human and mouse B-cell lymphomas. These data suggest that, in addition to TRAF2- and cIAP1/2-mediated ubiquitination, cFLIP-regulated and caspase-8-dependent limited cleavage of RIP1 is a new layer of mechanism that promotes NF-κB activation and cancer cell survival.
Citation Format: Hasem Habelhah, Lauren Workman, Laiqun Zhang. Molecular mechanisms by which cFLIP overexpression regulates TRAIL-induced NF-κB activation and lymphoma survival. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2281. doi:10.1158/1538-7445.AM2014-2281