bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4375: High hydrostatic pressure modified potato patatin induces apoptosis like cell death in human colorectal adenocarcinoma (HT-29) cell line
Authors: Elahi Rizwan , MU Tai Hua 
Published: August 2018

Abstract
The current study assessed the anticancer activity of HHP-induced potato patatin on human colorectal adenocarcinoma (HT 29) cell line in vitro. Cell proliferation, apoptosis, necrosis and autophagy were investigated. HHP treatment inhibited HT-29 cell line proliferation in a dose a dependent manner. IC50 values showed antiproliferative activity (59.1%) at 4 mg mL-1 for HHP-induced patatin at 450 MPa. Flow cytometric analysis indicated that HHP-induced patatin at 450 MPa was the potent inducer of in vitro apoptotic cell death and showed significant (p&lt;0.05) accumulation in S-phase followed by patatin pressurized at 550 MPa. Surface charge of patatin decreased with the increase in pressurization up to 350 MPa level, while at 450 MPa zeta potential value increased to (-13 mV) and (-11 mV) respectively. Overall, results indicated that 450 MPa patatin is a strong inhibitor of HT-29 and a potent inducer of apoptotic cell death. Thus, HHP treatment is an effective method for structural modification of patatin which ultimately enhance the anticancer potential against colorectal cancer cells.
Citation Format: Rizwan Elahi, Tai Hua MU. High hydrostatic pressure modified potato patatin induces apoptosis like cell death in human colorectal adenocarcinoma (HT-29) cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4375.
Abstract 4385: p53 activation induces a targetable dependence on FLIPL
Authors: McIntyre Alexander , Lees Andrea , Falcone Fiammetta , Gregg Gemma , Tamas Sessler , Quinn Gerard , Crawford Nyree , McArt Darragh , Dunne Phillip , Lawler Mark , Daniel Longley B. , McDade Simon S. 
Published: August 2018

Abstract
Background
The tumor suppressive functions of the p53 transcription factor are inactivated via mutations or suppressed through non-mutational mechanisms in almost all cancer cells. A better understanding of the mechanisms through which p53 differentially regulates cell cycle arrest and cell death is important to maximize benefits from wild-type p53-dependent therapeutic strategies
Methods
A panel of matched p53 wild-type and deficient colorectal cancer cell line models were studied, using Nutlin-3A and Oxaliplatin as direct and indirect p53 activating agents respectively. A number of molecular (Western blot, RT-PCR), phenotypic (cell death) and genomic analyses were used to investigate the importance of p53 and its downstream transcriptional programs.
Results
Here, we report that activation of pro-apoptotic p53 targets in colorectal cancer cells imposes a critical targetable dependence on the long splice form of the caspase-8 regulator FLIP (FLIPL) for survival. p53 binds the promoter of the FLIP gene (CFLAR) and upregulates FLIPL expression in response to the p53 agonist Nutlin-3A in a manner dependent on HDAC1/2/3 activity. As such, preventing FLIPL upregulation with the clinically relevant HDAC1/2/3-selective inhibitor Entinostat promotes apoptosis induction in response to Nutlin-3A (or p53-activating chemotherapy), which otherwise predominantly induces growth arrest despite upregulating a range of pro-apoptotic target genes. Cell death in response to Nutlin-3A in FLIPL-depleted cells is primarily mediated via caspase-8. However, in the absence of caspase-8, apoptosis is delayed, but not prevented and is mediated via caspase-10. Of note, the cell death induced in both caspase-8-proficient and -deficient cells is mediated via TRAIL-R2 in a ligand-independent manner.
Conclusion
In summary, this work has uncovered novel, clinically-relevant biology, in which p53-mediated upregulation of FLIPL primes cells for TRAIL-R2-mediated apoptosis and identifies FLIPL as a key target for overcoming resistance to p53-stabilising agents in p53 wild-type cancers. Moreover, we show the potential of combining Nutlin-3A (or other p53 activating chemotherapies) with the clinically relevant Class I HDAC inhibitor Entinostat for the treatment of p53 wild-type CRC, and identify FLIPL as a critical p53-induced signaling node, the inhibition of which is necessary to promote Nutlin-3A-induced apoptosis.
Citation Format: Alexander McIntyre, Andrea Lees, Fiammetta Falcone, Gemma Gregg, Sessler Tamas, Gerard Quinn, Nyree Crawford, Darragh McArt, Phillip Dunne, Mark Lawler, Longley B. Daniel, Simon S. McDade. p53 activation induces a targetable dependence on FLIPL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4385.
Abstract 4386: Regulation of FIP200 by Her2 and its role in Her2-driven mammary tumors
Authors: Hao Mingang , Guan Jun-Lin 
Published: August 2018

Abstract
Autophagy has been shown to play both tumor promoting and suppressive roles in various cancers, although the underlying mechanisms are not well understood. Compared to other subtypes of breast cancer (BCa), Her2+ BCa displays a lower autophagy gene signature, suggesting a potentially tumor suppressive function of autophagy in this subtype of BCa. FIP200 is a component of the ULK1/ATG13/FIP200/Atg101 complex essential for autophagy induction in mammalian cells, and our previous studies showed that Fip200 deletion suppressed BCa in MMTV-PyMT mouse model. Indeed, analysis of TCGA database showed that higher FIP200 expression correlated with decreased survival of BCa patients including all subtypes. In contrast, in Her2+ BCa population specifically, higher expression of FIP200 correlated with better patient survival, suggesting a differential function of FIP200. To uncover the role of FIP200 and autophagy in Her2+ BCa, we studied Fip200 in MMTV-Neu mouse tumor cells that model Her2+ BCa. We found that inhibiting autophagy by deletion of Fip200 or Atg13 using Crispr-Cas9 led to increased migration and partial EMT for MMTV-Neu cells. Further, deletion of Fip200 or Atg13 as well as autophagy inhibition by Spautin1 significantly enhanced β-catenin/LEF1/TCF reporter activity, which may promote cell migration and EMT. These changes in Fip200-null tumor cells could be rescued by re-expression of ectopic FIP200, excluding any potential off-target effects of gene knockout. We also found that Her2 knockdown or lapatinib treatment of MMTV-Neu cells increased Fip200 expression and autophagy. Together, these results raised the interesting
possibility that Her2 may promote tumor development and/or progression at least in part by reducing FIP200 expression to inhibit autophagy, which might play a tumor suppressive role in Her2-driven BCa.
Citation Format: Mingang Hao, Jun-Lin Guan. Regulation of FIP200 by Her2 and its role in Her2-driven mammary tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4386.
Abstract 4389: HEXIM1 is a negative regulator of H. pylori-induced BIRC3 enhancer RNA
Authors: Sheppard Donald R. 
Published: August 2018

Abstract
The bacterium Helicobacter pylori inhabits the human stomach and is responsible for a number of pathologies, including being strongly associated with the development of gastric adenocarcinoma. H. pylori inhibits apoptosis in gastric cells, but the mechanism is poorly understood. We investigated how H. pylori inhibits apoptosis using cultured G27-strain H. pylori to stimulate cancer cell lines, and apoptosis was induced with Raptinal. We found that H. pylori induces the transcription of the apoptosis-inhibiting protein cIAP2, and this induction is sufficient to inhibit apoptosis in stimulated cells. We found an enhancer region upstream of the gene that codes for cIAP2 (BIRC3). H. pylori induces expression of RNA from this enhancer, and RNAi treatment targeting this eRNA inhibited induction of the BIRC3 mRNA. Chromatin immunoprecipitation revealed that positive transcription elongation factor b (P-TEFb) is recruited to the enhancer following H. pylori stimulation, and RNA polymerase II is activated. We found that the negative regulator of transcription HEXIM1 inhibits P-TEFb recruitment and eRNA production. HEXIM1 also inhibits BIRC3 mRNA transcription, cIAP2 protein induction and H. pylori's anti-apoptotic effect. Together, these findings indicate that H. pylori inhibits apoptosis induction in cultured cells, and this inhibition is mediated by the induction of BIRC3/cIAP2. H. pylori stimulates the production of RNA from the enhancer region of BIRC3, which is required for the induction of the gene, and the eRNA production is regulated by HEXIM1 and P-TEFb.
Citation Format: Donald R. Sheppard. HEXIM1 is a negative regulator of H. pylori-induced BIRC3 enhancer RNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4389.
Abstract 4390: Developing methods for investigating cold atmospheric plasma effects on cervical cancer
Authors: Sova Nicole J. , Zhu Yonry , Mitchell Quinn O. , Lanier Ariel L. , Burnette David , Burdick Monica M. 
Published: August 2018

Abstract
Cold atmospheric plasma (CAP) has been suggested for use as a novel cancer therapeutic due to its reported ability to induce cell-specific death. Cervical cancer is the fourth most common cancer in women. Its prevalence and accessibility for topical treatment make cervical cancer an ideal target for CAP treatments. Despite its potential impact, effects of CAP in biological systems are not well understood. To better understand the viability of CAP as a therapy, this project investigated in vitro cellular responses induced by CAP treatment within cancerous cervical cells (SiHa) and non-cancerous cervical (Ect1/E6E7 and End1/E6E7) and vaginal cells (VK2/E6E7).
Plasma is a state of ionized gas, produced using a controlled electric field or extreme heat. CAP, however, is a subset of plasma that is produced near 1 atm and 40oC. This allows for CAP treatment of biological systems without heating-induced effects. A dielectric barrier discharge plasma pen was developed for this study. Plasma modeling was conducted in order to predict the reactive species present in the system. CAP treatments were performed on cells for 30 seconds using a helium carrier gas at a flowrate of 1 L/min and a DC power supply with input settings of 10kV, 1µs, and 0.1A.
Cell vitality assays demonstrated induced cell death following exposure to CAP treatment in both cancerous and noncancerous cervical cells as indicated by flow cytometric analysis and florescence microscopy. CAP treatment induced cell death in 76 ± 8% of treated cancerous, SiHa, cells. In comparison, noncancerous cell lines Ect1/E6E7, End1/E6E7, and VK2/E6E7 underwent 49 ± 8%, 42 ± 13%, and 51 ± 7% cell death, respectively. Flow cytometry characterization and wound healing assays indicate that CAP treatment does not significantly affect the expression of investigated cell surface adhesion molecules or cell migration. Cells were treated with helium carrier gas as the negative control and hydrogen peroxide as an induced death control.
Altered levels and locations of uptake of FITC and quantum dots following CAP treatment suggest modification of cell membranes as compared to carrier gas treatment controls. Adjustments in membrane permeability may be a mechanism through which CAP treatment increases exposure to apoptotic triggers.
In conclusion, comprehensive understanding of CAP effects on cancerous and non-cancerous cells could lead to the development of effective CAP-based therapies for cervical cancer.
Citation Format: Nicole J. Sova, Yonry Zhu, Quinn O. Mitchell, Ariel L. Lanier, David Burnette, Monica M. Burdick. Developing methods for investigating cold atmospheric plasma effects on cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4390.
Abstract 4394: Novel edible medicinal plant induced cytotoxic and apoptotic effects on ovarian cancer cells
Authors: Mbemi Ariane T. 
Published: August 2018

Abstract
Ovarian cancer (OC) is the leading cause of death in gynecologic cancer and the fifth most common form of cancer diagnosed among women. Caucasians have a higher incidence and mortality rate compared to African-Americans. The low survival rate of ovarian cancer among patients is caused by the fact that ovary organs are located inside the pelvic region in the female reproductive system; many cases are diagnosed in advanced stage, when cancer has already metastasized beyond the ovaries. Consequently, there is an urgent need to prevent ovarian cancer at the early stage and provide effective treatment. Herbal medicine with lesser or no side effect is currently considered as an alternative cancer treatment because it possesses many bioactive compounds essential to destroy cancer cells. A preliminary study in our laboratory demonstrates that extracts of Vernonia species have antitumor activities against cancer cells. Therefore, our overall goal in this study was to test the therapeutic mechanisms of a Vernonia species (an edible medical plant) in the treatment of ovarian cancer. To reach our goal, we tested the cytototic and apoptotic effects of the Vernonia species on OVCAR-3 cells. Data generated from the trypan blue test and MTT assay demonstrated that extracts of Vernonia species exhibited significant growth-inhibitory effects on OVCAR-3 cells. Oxidative stress biomarkers showed slight decrease in the production of malondialdehyde (MDA) levels and an increase in catalase activity and glutathione peroxidase in treated cells compared to the control group. Further experiments, including cell morphology and apoptosis analysis, showed that VA caused growth-inhibitory effects on OVCAR-3 cells through cell cycle arrest at the Go/G1 checkpoint and activation of caspase-3 activity leading to apoptosis. Collectively, findings from this study provide convincing scientific evidence that the Vernonia species tested here may represent a potential anticancer candidate against ovarian cancer.
This research work was supported by a grant from the National Institutes of Health (Grant No. NIMHD-G12MD007581).
Citation Format: Ariane T. Mbemi. Novel edible medicinal plant induced cytotoxic and apoptotic effects on ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4394.
Abstract 4395: KP-1339 (IT-139) induces the hallmarks of immunogenic cell death in a colon cancer 3D model in vitro
Authors: Wernitznig Debora , Favero Giorgia Del , Kiakos Konstantinos , Harrer Nathalie , Machat Herwig , Marko Doris , Jakupec Michael , Sommergruber Wolfgang , Keppler Bernhard K. 
Published: August 2018

Abstract
Chemotherapeutic drugs exert their activity by directly killing tumor cells through a variety of cellular targets eventually leading to apoptosis. Apoptosis is regarded as non-inflammatory and non-immunogenic, however, recent data confirm that the induction of damage-associated molecular patterns by dying cancer cells treated with certain chemotherapeutic agents, such as oxaliplatin, lead to their recognition by the immune system, and result in dendritic cell maturation and immune responses, a mechanism described as Immunogenic Cell Death (ICD). The main hallmarks of ICD are: Calreticulin (CRT) exposure on the cell membrane and release of high mobility group box-1 (HMGB-1) and ATP from dying cells. We have recently shown that the mode of action of KP-1339, a clinically investigated ruthenium-based metal complex, involves the enhancement of endoplasmic reticulum stress (ERS) and the induction of apoptosis-like events. We next investigated the ability of KP-1339 to trigger ICD. There is currently no reliable method to study ICD in vitro, and therefore we aimed at a more suitable model that better mimics the tumor microenvironment in comparison to 2D monolayer cultures. For this reason, ICD was assessed in human colorectal cancer HCT-116 3D multicellular spheroids in vitro. We demonstrate that spheroids treated with KP-1339 activate the PERK/Phospho-eIF-2alpha pathway of the ERS, a prerequisite for CRT exposure on the cell membrane. HMGB1 protein levels decrease considerably during a 72 hours drug treatment, as shown by Immunoblotting, suggesting the depletion of the protein. Additionally, treated spheroids released significantly more ATP than untreated controls. Immunofluorescence of cryosections of KP-1339 treated spheroids stained for CRT and HMGB1 confirmed the above observations and, clearly showed the translocation of CRT to the cell membrane.
In conclusion, we have established a 3D tumor spheroid model as an alternative to the 2D monolayer cultures to study ICD in vitro. This model more closely resembles the tumor microenvironment and recapitulates relevant aspects of the in vivo situation. We successfully employed this model to demonstrate that the clinically investigated compound KP-1339 triggers the main hallmarks of ICD, which suggests enhanced induction anti-tumor immunity in colorectal cancer.
Citation Format: Debora Wernitznig, Giorgia Del Favero, Konstantinos Kiakos, Nathalie Harrer, Herwig Machat, Doris Marko, Michael Jakupec, Wolfgang Sommergruber, Bernhard K. Keppler. KP-1339 (IT-139) induces the hallmarks of immunogenic cell death in a colon cancer 3D model in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4395.
Abstract 4396: Targeting survivin to overcome docetaxel resistance in prostate cancer
Authors: Peery Robert C. 
Published: August 2018

Abstract
Despite therapeutic advancements, castration-resistant prostate cancer (CRPC) remains the second most common cause of cancer-related mortality in men. Docetaxel is the first cytotoxic agent to show modest improvements in overall survival rate in patients with CRPC. Unfortunately, over half of these patients do not respond to treatment and ultimately all develop resistance. The mechanism mediating docetaxel resistance remains unknown. However, survivin, an inhibitor of apoptosis (IAP) family member, and known mediator of chemo-resistance has been previously associated with docetaxel resistance, as inhibition of survivin expression sensitized prostate cancer cells to docetaxel in vitro, and a small molecule inhibitor targeting survivin expression led to a significant regression in prostate cancer xenograft tumors when given in combination with docetaxel. However, how survivin may mediate docetaxel resistance in prostate cancer remains unknown. In this study, we tested the hypothesis that overexpression of nuclear survivin contributes to docetaxel resistance in prostate cancer cells. First, utilizing western blot to assess protein level and methylene blue assays to determine ability to proliferate under cytotoxic conditions, we found that survivin expression and docetaxel IC50 correlates strongly in five prostate cancer cell lines. Furthermore, using paired parental drug sensitive and stepwise selected docetaxel resistant cell lines, we determined that resistant cells overexpress survivin as compared to parental cells, and knockdown of survivin decreases resistance to docetaxel. Our studies suggest that survivin is likely implicated in CRPC and treatment with a direct survivin inhibitor may sensitize resistant cells to docetaxel. We are in the process of determining how this IAP may mechanistically mediate docetaxel resistance.
Citation Format: Robert C. Peery. Targeting survivin to overcome docetaxel resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4396.
Abstract 4405: Pharmacologic profile of INT-1B3: A novel synthetic microRNA 193a-3p mimic for therapeutic intervention in oncology
Authors: Yahyanejad Sanaz , Gunst Thijs de , Schultz Iman , Boer Harm den , Raimo Monica , Telford Bryony , Vos Rogier , Pinxteren Laurens van , Schaapveld Roel , Janicot Michel 
Published: August 2018

Abstract
MicroRNAs (miRNAs) are a family of small, non-coding RNAs and serve as small snippets of genetic material that regulate gene expression. As a result, miRNAs modulate a wide range of biological processes including; cell cycle control and apoptosis, cell signaling and differentiation, cell adhesion and motility. Thus, it is not surprising that their misregulation is linked to cancer initiation, treatment response, and metastasis. Due to the inherent ability of miRNAs to concurrently target multiple pathways, their therapeutic potential to be used as anti-cancer drugs is attractive. In this study, we are investigating the mode of action and development of a novel synthetic miRNA mimic (INT-1B3) as a therapeutic candidate for substitution and functional restoration of a depleted miRNA in variety of cancers. To identify miRNAs that control the survival of cancer cells, we performed a functional miRNA screening in which a wide range of relevant miRNAs were selected and miR-193a-3p was chosen as the potential candidate for further preclinical characterization. Compelling evidence demonstrate a tumor suppressor function for miR-193a-3p in many cancer types and link its reduced expression with cancer, metastasis and therapy resistance. Consistent with the described role for miR-193a-3p in literature, our cell-based assays conducted in various experimental tumor cell systems demonstrated efficient target engagement leading to reduced cell proliferation/survival, cell cycle arrest and induction of apoptosis, inhibition of cell motility as well as a potential immune-modulatory role (via adenosine-mediated tumor immune evasion). Furthermore, development of a novel lipid nanoparticle-based formulation as an efficient delivery system demonstrated a marked anti-tumor activity of INT-1B3 as single agent following systemic administration in tumor-bearing mice. Robust tumor growth inhibition in these experimental tumor models is correlated and consistent with efficient target engagement in tumor cells and relevant organs. We are currently investigating the in vitro and in vivo effect of INT-1B3 in variety of cancer types including hepatocellular carcinoma, melanoma and triple negative breast cancer. Our data thus far supports an anti-tumor role for INT-1B3 and encourages further preclinical and clinical investigation.
Citation Format: Sanaz Yahyanejad, Thijs de Gunst, Iman Schultz, Harm den Boer, Monica Raimo, Bryony Telford, Rogier Vos, Laurens van Pinxteren, Roel Schaapveld, Michel Janicot. Pharmacologic profile of INT-1B3: A novel synthetic microRNA 193a-3p mimic for therapeutic intervention in oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4405.