bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2942: Acetylation of intracellular protein induces apoptotic cell death in Aspirin-treated human breast cancer cells.
Authors: Lee Yu Ran , Jeon Byeong Hwa , Choi Sunga 
Published: August 2014

Abstract
Acetylation is one of the dynamic post-translational modification of lysine residues on protein determining the structure, function and intracellular localization that plays an important role in the signal transduction pathways related to diverse cell functions - proliferation, cell death, and differentiation as well as transcriptional regulation. Recently, it has been reported that acetylating agents including chemical histone deacetylase inhibitors and plant polyphenols lead to the increased acetylation of histone and non-histone proteins, which induces to rapid cancer cell death. In this present study, we are focused on molecular mechanism of cell death in two Aspirin-treated human breast cancer cells, MCF-7 and MDA-MB-231. Trichostatin A (TSA) treatment was combined for maintaining acetylation of intracellular proteins at 0.1 μM concentration, which was not caused cell death itself. It was observed that Aspirin/TSA treatment caused the significant inhibition of cell growth in a dose- and time-dependent manner in both MDA-MB-231 and MCF-7 cells. The induced cell death in MDA-MB-231 by Aspirin/TSA treatment was associated with several specific features of apoptosis, which were proved by biochemical assays containing DNA fragmentation, Annexin V staining and cell cycle analysis. On the other hand, the exposure of MCF-7 to Aspirin/TSA caused necrotic rather than apoptotic mechanism judged by DNA fragmentation assay. These results suggest that different cell death pathway in two breast cancer cell lines is implicated in acetylated protein mediated signals. Previous reports suggest sporadic tumor cell necrosis is associated with extracellular release of cellular protein such as the high mobility group box 1 and may activate innate immune system. Interestingly, we confirmed secretory protein in cell-culture supernatant by immunoprecipitation using anti-acetyllysin antibody. Secretion of the acetylated protein was elevated dose- and time- dependent manner after Asprin treatment. Although extracellular role of the secretory protein in response to acetylation has not been clearly identified yet, this acetylated protein may be involved in initiation of apoptotic cell death signals and/or activating innate immune response. Taken together, theses results indicated that acetylated protein plays an essential role in anti-tumorigenesis in response to acetylating agent such as Aspirin.
Citation Format: Yu Ran Lee, Byeong Hwa Jeon, Sunga Choi. Acetylation of intracellular protein induces apoptotic cell death in Aspirin-treated human breast cancer cells. [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 2942. doi:10.1158/1538-7445.AM2013-2942
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2945: Anti-tumor effect of insulin-like growth factor-1 receptor inhibition in head and neck squamous cell carcinoma.
Authors: Khalil Ashraf A. , Axelrod Mark J. , Hubbard Matthew A. , Maxwell Anne K. , Taniguchi Linnea E. , Mendez Rolando E. , Jameson Mark J. 
Published: August 2014

Abstract
Back ground: Insulin-like growth factor-1 receptor (IGF1R) activity is upregulated in a variety of human cancers and IGF1R signaling has been implicated as a mechanism of resistance to various cancer therapies, including radiotherapy, cytotoxic chemotherapy, and targeted molecular therapy. We have demonstrated that IGF1R activation can induce resistance to targeted therapy of head and neck squamous cell carcinomas (HNSCCs) using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Targeting the IGF1R by selective small molecule kinase inhibition may thus hold promise as an adjuvant treatment for HNSCC.
Aims: (1) To assess the anti-tumor effects of two IGF1R/insulin receptor TKIs, BMS-754807 and OSI-906, in multiple HNSCC cell lines in vitro. (2) To evaluate the effect of combined IGF1R and EGFR inhibition in HNSCC cell lines in vitro.
Methods: The effect of IGF1R inhibition on cell proliferation, viability, survival, and apoptosis was assessed using alamarBlue, trypan blue exclusion, clonogenic, and flow cytometric assays in 9 HNSCC cell lines. Alterations in downstream IGF1R signaling were assessed by standard immunoblot. The impact of combining an EGFR-TKI with an IGF1R-TKI was measured.
Result: Both BMS-754807 and OSI-906 inhibited IGF1R phosphorylation at 200 nM. Complete inhibition of the phosphorylation of IRS-1 and Akt required higher concentrations. Both inhibitors slowed proliferation, decreased cell viability, and decreased cell survival in all 9 cell lines. The EC50 to inhibit proliferation was in the range of X to X microM for BMS-754807 and X to X microM for OSI-906. Both drugs induced apoptosis in HNSCC tumor cell lines based on flow cytometric analysis of caspase-3 cleavage and PARP cleavage. In combination with gefitinib and lapatinib, BMS-754807 and OSI-906 were capable of synergistic growth inhibition.
Conclusion: Inhibition of IGF1R activity using the selective TKIs BMS-754807 and OSI906 has an antitumor effect on HNSCC cells in vitro. These drugs are synergistic with EGFR-TKIs and co-targeting the two receptors may represent an approach to overcoming clinical resistance to targeted anti-growth factor therapy in HNSCC.
Citation Format: Ashraf A. Khalil, Mark J. Axelrod, Matthew A. Hubbard, Anne K. Maxwell, Linnea E. Taniguchi, Rolando E. Mendez, Mark J. Jameson. Anti-tumor effect of insulin-like growth factor-1 receptor inhibition in head and neck squamous cell carcinoma. [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 2945. doi:10.1158/1538-7445.AM2013-2945
Abstract 2947: PARP-1 regulates death receptor 5-mediated apoptosis in pancreatic cancer.
Authors: Yuan Kaiyu , Sun Yong , Zhou Tong , McDonald Jay , Chen Yabing 
Published: August 2014

Abstract
Pancreatic cancer is a highly malignant tumor with limited therapy and poor prognosis. Activation of death receptors (DR)-induced apoptotic pathways using antibodies or agonists for the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy. However, most pancreatic tumors are resistant to TRAIL therapy. The present studies aimed to identify combination therapies that enhance the efficacy of TRAIL therapy by sensitizing resistant pancreatic cancer cells to TRAIL-induced apoptosis, and to investigate the underlying mechanisms.
Using TRA-8, a monoclonal agonistic antibody specific for DR5, we demonstrated that TRA-8 induced apoptosis of 60% and 83% of BxPc-3 and MiaPaCa-2 pancreatic cancer cells in 24 hours. By contrast, only 20% and 24% of PANC-1 and Suit-2 cells underwent apoptosis in response to TRA-8 (n=3), despite the fact that they express high levels of the DR5 receptor. The expression of poly(ADP-ribose) polymerase-1 (PARP-1) was higher in the PANC-1 and Suit-2 cells than that BxPc-3 and MiaPaCa-2 cells, which may contribute to their resistance to TRA-8-induced apoptosis. Inhibition of PARP-1 with a pharmacologic inhibitor (PJ-34) sensitized PANC-1 to TRA-8 induced apoptosis in a dose-dependent manner. Furthermore, small interfering RNAs specifically knocking down PARP-1 in PANC-1 cells enhanced TRA-8-induced apoptosis in vitro by 2.5 fold, as well as the efficacy of TRA-8 therapy on tumorigenesis of PANC-1 cells in a mouse xenograft model by 3.8 fold (n=8, p&lt;0.01). PARP-1 knockdown increased TRA-8-induced activation of caspase-8 in the death-induced signaling complex (DISC). Immuoprecipitation with DR5 antibody identified the recruitment of PARP-1 and PARP1-mediated protein poly-ADP-ribosylation(pADPr) modification in the DR5-associated DISC, which was associated with caspase 8 activation in the DISC. Our studies determined a novel function of PARP-1, independent of its known function in DNA repair, in regulating caspase 8 activation in the DISC. These results not only provide novel molecular insights into the function of PARP-1 in regulating the extrinsic apoptosis machinery, but also support the intervention of combining PARP inhibitors with death receptor agonists to enhance the efficacy of pancreatic cancer therapy.
Citation Format: Kaiyu Yuan, Yong Sun, Tong Zhou, Jay McDonald, Yabing Chen. PARP-1 regulates death receptor 5-mediated apoptosis in pancreatic cancer. [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 2947. doi:10.1158/1538-7445.AM2013-2947
Abstract 2950: Deletion of TRADD sensitizes oxidative stress-induced necrotic cell death.
Authors: Koo Ki-Bang , Lee Da-gyum , Oh Ji-Yoon , Lee Yun-Sun , Kim You-Sun 
Published: August 2014

Abstract
TNF Receptor-Associated Death Domain (TRADD) is an essential mediator of TNF receptor-1-mediated TNF signaling and is responsible for recruitment of other effector proteins. Recruitment of these adaptor proteins leads to the activation of MAP kinases and NF-kB, as well as cell death. it is well known that aspect of ROS biological effects is their regulatory roles on cell death to function as direct activator cell death or as second messengers in the cell death processes. ROS may initiate cell death processes through affecting various signaling cascade. Several studies on the oxidative stress-induced cell death has shown that some of the key TNF signaling molecules serve as the molecular targets of ROS in cell death. However, there is no report concerning whether TRADD has a function in oxidative stress-induced cell death. The availability of TRADD deficiency mice let us investigate the physiological functions of TRADD on oxidative stress-induce cell death. In this study, we found that TRADD deficiency renders cells more susceptible to oxidative stress-induced cell death through the persistent activation of JNK.
Citation Format: Ki-Bang Koo, Da-gyum Lee, Ji-Yoon Oh, Yun-Sun Lee, You-Sun Kim. Deletion of TRADD sensitizes oxidative stress-induced necrotic cell death. [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 2950. doi:10.1158/1538-7445.AM2013-2950
Abstract 2951: DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.
Authors: Liu Fang , Korc Murray 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a poor prognosis that is characterized by marked chemoresistance to a broad spectrum of chemotherapeutic drugs, as a consequence of intrinsic cell-autonomous factors, and extrinsic stroma-associated factors. Dual specificity protein phosphatase 1 (DUSP1) has been reported to be overexpressed in pancreatic cancer cells in PDAC. Moreover, DUSP1 was shown to be essential for efficient in vitro colony formation and in vivo tumorigenicity, indicating that DUSP1 may contribute to the biological aggressiveness of PDAC. However, it is not known whether DUSP1 overexpression contributes to PDAC chemoresistance. Using BxPC3 and COLO-357 human pancreatic cancer cells, we show that gemcitabine activated c-JUN N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38 MAPK), key kinases in two major stress-activated signaling pathways. Activation of JNK and p38 MAPK was associated with increased apoptosis, as evidenced by increased cleavage of PARP and Caspase 3. However, gemcitabine also enhanced DUSP1 transcription, as demonstrated by increased DUSP1 mRNA levels, and increased RNA polymerase II loading at both DUSP1 promoter and gene body. Moreover, shRNA-mediated inhibition of DUSP1 enhanced JNK and p38 MAPK activation and sensitized both cell lines to gemcitabine. Taken together, these results suggest that gemcitabine-mediated upregulation of DUSP1 contributes to a negative feedback loop that attenuates its beneficial actions on stress pathways and apoptosis, raising the possibility that targeting DUSP1 in PDAC may have the dual advantage of suppressing proliferation while enhancing gemcitabine chemosensitivity.
Citation Format: Fang Liu, Murray Korc. DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine. [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 2951. doi:10.1158/1538-7445.AM2013-2951
Abstract 2952: The PKC-iota inhibitor ICA-1 combined with TRAIL for glioblastoma therapy.
Authors: McCray Andrea N. , Desai Shraddha , Acevedo-Duncan Mildred 
Published: August 2014

Abstract
Glioblastoma multiforme is a very aggressive brain tumor. Temozolimide is the standard clinical therapy following surgery which offers a limited survival advantage. The low survival rates of glioblastoma patients require further investigation into pre-clinical combination therapy options with apoptosis abilities. One such chemotherapeutic approach is the use of the novel PKC-iota inhibitor, ICA-1, combined with rhTRAIL. T98G or U87 glioblastoma cells were treated with ICA-1 for 48h or 72h, respectively, with or without rhTRAIL in a 24-well format. Based on flow cytometric analysis, the overall apoptosis rate for the T98G cells exposed to ICA-1 plus TRAIL was the most significant with no distinction between early and late apoptosis rates. In addition, the immunofluorescence analysis showed higher T98G cell death for the combination therapy. Further flow cytometric analysis showed that ICA-1 plus TRAIL generated significantly more late apoptosis for U87 cells than any other treatment. The mechanism of action for this combinatorial therapy is currently under investigation. However, our in vitro data demonstrated that ICA-1 plus TRAIL induced 60-70% apoptosis in U87 glioblastoma cells and T98G glioblastoma cells which may offer a better survival advantage in pre-clinical animal models.
Citation Format: Andrea N. McCray, Shraddha Desai, Mildred Acevedo-Duncan. The PKC-iota inhibitor ICA-1 combined with TRAIL for glioblastoma therapy. [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 2952. doi:10.1158/1538-7445.AM2013-2952
Abstract 2953: Inhibition of calmodulin enhances TRA-8-induced apoptosis in pancreatic cancer cells .
Authors: Yuan Kaiyu , Zhou Tong , McDonald Jay , Chen Yabing 
Published: August 2014

Abstract
Current chemotherapy and radiotherapy are not curative for pancreatic cancer. Tumor necrosis factor-related apoptosis-inducing ligand or agonist antibodies for death receptor 4/5 have been shown to be a promising cancer therapy. 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. We have previously demonstrated that calmodulin (CaM) antagonists enhance the Fas death receptor-mediated apoptosis pathway. Therefore, we investigated whether inhibition of CaM might affect DR5-induced apoptotic signaling in pancreatic cancer cells.
We found that CaM antagonists, trifluoperazine (TFP) and tamoxifen (TMX), dose dependently enhanced TRA-8-induced apoptosis of the TRA-8-resistant PANC-1 pancreatic cells. Consistently, TFP and TMX increased TRA-8-induced activation of caspase 8, caspase 9 and caspase 3. Pretreatment of PANC-1 with Z-IETD-FMK, the caspase-8 inhibitor, decreased TFP-enhanced apoptosis by 2 fold, and markedly decreased caspase 3 activation. Immunoprecipitation analysis of the DR5-induced death inducing signaling complex (DISC) identified the interaction of CaM with DR5. Activation of DR-5 by TRA-8 increased the recruitment of CaM into the DISC, which was inhibited by TFP. In addition, TFP decreased the recruitment of the adaptor protein, FADD, and other DISC proteins that regulate cell survival, including Src and the caspase-8 inhibitory protein FLIP. Collectively, these results support an important role for CaM in DR5-induced DISC formation, thus regulating DR5-mediated survival and apoptotic signaling in pancreatic cancer cells.
In summary, we have demonstrated that CaM antagonists sensitize pancreatic cancer cell to TRA 8-induced apoptosis, and that CaM binding to DR5 regulates DR5-induced DISC formation. Defining the function of CaM in regulating DR5-induced signaling pathways may lead to novel therapeutic strategies including the use of CaM antagonists with TRA-8 as combination therapy for pancreatic cancer.
Citation Format: Kaiyu Yuan, Tong Zhou, Jay McDonald, Yabing Chen. Inhibition of calmodulin enhances TRA-8-induced apoptosis in pancreatic cancer cells . [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 2953. doi:10.1158/1538-7445.AM2013-2953
Abstract 2959: Celarstrol enhances TNF-induced neuroblastoma cells death by promoting ROS-mediated programmed necrosis.
Authors: Zhao Ming , Lin Song , Cheng Xiang , Chen Guozhu , Yu Xiaodan 
Published: August 2014

Abstract
Celastrol is an active ingredient of the traditional Chinese medicinal plant Tripterygium Wilfordii, which exhibits significant antitumor activity in different cancer models in vitro and in vivo. Previous studies have showed that celastrol kills cancer cells by inducing apoptosis, in this study, we reported that celastrol has potential to enhance TNF-induced necroptosis in SH-SY5Y neuroblastoma cells. Low dose of TNFα plus celastrol induced remarkable cell death which could be prevented by RIP1 kinase inhibitor Necrostatin-1, but exacerbated by caspase inhibitor Z-VAD-FMK. The mechanism for celastrol to enhance TNF-induced necroptosis involves promoting prolonged JNK activation and inducing ROS accumulation. TNFα plus celastrol induced cell death and mitochondrial outer membrane permeabilization (MOMP) could be reversed by ROS scavenger BHA. In addition, Mdivi-1, an inhibitor of mitochondrial fission protein Drp-1, could also block TNFα plus celastrol induced cell death and MOMP, which is consistent with previous elucidation that RIP1/RIP3 mediated cell death signal through Drp-1 to induced necroptosis. The effect of celastrol on enhancing cancer cells programmed necrosis may provide a new way to overcome the resistance chemotherapy induced by evading apoptosis in some cancer cells.
Citation Format: Ming Zhao, Song Lin, Xiang Cheng, Guozhu Chen, Xiaodan Yu. Celarstrol enhances TNF-induced neuroblastoma cells death by promoting ROS-mediated programmed necrosis. [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 2959. doi:10.1158/1538-7445.AM2013-2959
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 296: 12-O-tetradecanoylphorbol-13-acetate (TPA) induces cell scattering by upregulating krüppel-like factor 4 (KLF4) through the PKCα-ERK signaling axis.
Authors: Lai Jun-Kai , Wu Han-Chung , Chang Chia-Che 
Published: August 2014

Abstract
Krüppel-like factor 4 (KLF4) is a C2H2 zinc-finger transcription factor known to regulate multiple cellular processes including cell proliferation, differentiation and stemness. Cell scattering is characterized by disruption of E-cadherin-mediated intercellular adhesion and acquisition of fibroblast-like morphology with increased motility and invasiveness, a cellular process reminiscent of epithelial-to-mesenchymal transition (EMT). We have previously demonstrated the involvement of KLF4 in hepatocyte growth factor (HGF)-induced cell scattering (Lai et al., J. Cell Sci., in press). Still, the question as to whether KLF4 is generally involved in cell-scattered response induced by other stimuli such as 12-O-Tetradecanoylphorbol-13-Acetate (TPA) has never been formerly addressed and thus the main focus of this study. Using human hepatocellular carcinoma cell line HepG2 as the cellular model, we herein presented evidence that KLF4 was clearly up-regulated following TPA stimulation. RT-PCR analysis and luciferase reporter assay revealed that both the mRNA and promoter activity of KLF4 was markedly increased by TPA, indicating that TPA up-regulated KLF4 at the level of transcription. Of note, knockdown of KLF4 severely impaired the level of TPA-induced HepG2 cell scattering, highlighting the requirement of KLF4 in TPA-induced scattered response. Additionally, we found that the promoting effect of TPA on KLF4 expression was clearly blocked when cells were pre-treated with the pan-PKC inhibitor Gö6983 as well as the PKCα-specific inhibitor Gö6976. Likewise, TPA-induced cell scattering and KLF4 up-regulation were ablated when ERK activity was inhibited by U0126. Taken together, our results defined the involvement of KLF4 in TPA-induced cell scattered response. Particularly, TPA engages the PKCα-ERK signaling axis to induce transcriptional up-regulation of KLF4, leading to the initiation of cell scattering. Our findings further implicate the possible involvement of KLF4 in other TPA-induced cellular responses such as cell migration and invasion.
Citation Format: Jun-Kai Lai, Han-Chung Wu, Chia-Che Chang. 12-O-tetradecanoylphorbol-13-acetate (TPA) induces cell scattering by upregulating krüppel-like factor 4 (KLF4) through the PKCα-ERK signaling axis. [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 296. doi:10.1158/1538-7445.AM2013-296