bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5470: Reversibility of therapy-induced senescence in non-small cell lung cancer as a model of cancer recurrence
Authors: Saleh Tareq , Cudjoe Emmanuel K. , Kyte S Lauren , Henderson Scott C. , Elmore Lynne W. , Gewirtz David A. 
Published: July 2017

Abstract
Disease recurrence at either primary or metastatic tumor sites arising from dormant tumors is largely responsible for the morbidity and mortality of many cancers. Although cellular quiescence has been proposed as a mechanism of dormancy, the nature of the growth arrest that allows tumor cells to re-emerge months or years after treatment has never been directly determined. The current work was designed to examine the hypothesis that the senescence induced by cancer chemotherapeutic drugs could be reversible, with implications for tumor dormancy and disease recurrence. Studies were performed using etoposide in models of non-small cell lung cancer (NSCLC). Exposure to etoposide at sublethal concentrations resulted in growth arrest accompanied by the induction of senescence and autophagy. Growth arrest was transient in that proliferative recovery was evident by day 7 post-etoposide exposure. Analysis of senescence based on β-galactosidase activity demonstrated that the restoration of proliferative capacity coincided with a decline in the extent of senescence. Real-time live microscopy demonstrated heterogeneous fates of senescent cells, where the bulk of the cell population remaining in a state of stasis, a subset of cells undergoing apoptosis, and a fraction of the large, flattened, and polyploid cells spontaneously entering into mitosis. Neither genetic nor pharmacological inhibition of autophagy influenced the senescence response to etoposide, the eventual proliferative recovery, or sensitivity to etoposide. These findings indicate that the induction and resolution of senescence is independent of the accompanying autophagy, and that the autophagy induced by etoposide is non-cytoprotective in function. These observations suggest that therapy-induced senescence may ultimately be a transient process in that at least a subpopulation of tumor cells can and will regain proliferative capacity. Consequently, therapy-induced senescence could potentially be studied as a model of tumor dormancy, and the reversibility of senescence as a model of disease recurrence.
Citation Format: Tareq Saleh, Emmanuel K. Cudjoe, S Lauren Kyte, Scott C. Henderson, Lynne W. Elmore, David A. Gewirtz. Reversibility of therapy-induced senescence in non-small cell lung cancer as a model of cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5470. doi:10.1158/1538-7445.AM2017-5470
Abstract 5471: LSD1 stimulates cell survival and epigenetic homeostasis via snail in hepatocellular carcinoma
Authors: Jo Yong Hwa , Nguyen Minh Nam , Choi Tae Gyu , Kim Sung Soo 
Published: July 2017

Abstract
HCC is the fifth most common malignancy in the world. HCC generally arises in the context of chronic liver diseases, or other metabolic, dietary or toxic factors. Hypoxia is a critical microenvironment in hepatcarcinogenesis. It occurs in series of distinct steps that include tumor cell invasion and proliferation. The process of EMT required for liver cancer cell invasion is regulated by a family of E-box-binding transcription repressors, which include Snail and Slug. Protein N, the first discovered histone methylase, is an epigenetic enzyme playing important role in regulation of gene expression and function by removing mono- or dimethyl moieties from H3K4 and H3K9. However, the molecular mechanisms underlying these biological behaviors have not been completely elucidated. Here, we present the first evidence that expression of Protein N was transcriptionally induced by Hif1 under hypoxia condition. We also showed that the up-regulated Protein N enhanced HCC cell survival and sustained epigenetic homeostasis via activating Snail under hypoxic conditions in vitro/in vivo. Furthermore, we revealed that Protein N/Snail stimulated Hif1 expression by a positive feedback loop. Conclusively, we elicited that Protein N is an essential mediator in epigenetic aberrances of HCC (This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2016R1D1A1B03933763)).
Note: This abstract was not presented at the meeting.
Citation Format: Yong Hwa Jo, Minh Nam Nguyen, Tae Gyu Choi, Sung Soo Kim. LSD1 stimulates cell survival and epigenetic homeostasis via snail in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5471. doi:10.1158/1538-7445.AM2017-5471
Abstract 5473: Towards a better understanding of MTH1 as a therapeutic target in RAS-driven cancer
Authors: Samaranayake Govindi J. , Troccoli Clara I. , Huynh Mai Q. , Win Andrew , Ji Debin , Kool Eric T. , Rai Priyamvada 
Published: July 2017

Abstract
Oncogenic RAS signaling-generated reactive oxygen species (ROS) drive tumor progression by the hyperactivation of proliferative, anti-apoptotic, and metastatic pathways. Elevated ROS levels however can also cause oxidative DNA damage, leading to oncogene-induced senescence (OIS) and cell death. To avoid such tumor-suppressive outcomes, RAS-driven tumors often upregulate redox-protective proteins. The collective research from our group over the last few years has shown that oncogenic RAS elevates expression of the mammalian 8-oxo-dGTPase MutT Homolog 1 (MTH1), which in turn enables evasion of OIS, promotes transformation efficiency, and facilitates tumorigenicity. Our prior work has therefore demonstrated that MTH1 is beneficial to the spectrum of RAS-driven transformation, and that its shRNA-mediated targeting in oncogenic RAS-harboring lung cancer cells produces robust tumor-suppressive outcomes. However the first wave of chemical MTH1 inhibitors has led to controversial and conflicting results regarding MTH1 as a chemotherapeutic target. Here we evaluate the benefit of MTH1 inhibitors in wildtype. vs. oncogenic KRAS expressing cells, and directly assess the effects of oncogenic KRAS as well as three recently developed inhibitors on MTH1 8-oxo-dGTPase activity. Our results support that introduction of oncogenic KRAS elevates both MTH1 expression and activity, presumably through its elevation of ROS levels, and thus sensitizes cells to MTH1 inhibitors. The degree of this sensitization has a complex dependence on residual 8-oxodGTPase activity in the different cells following treatment with the MTH1 inhibitors, alternate antioxidant responses, and induction of different tumor suppressor pathways. Our data therefore highlight the importance of evaluating the molecular contexts and outcomes of MTH1 inhibition when determining its utility as a chemotherapeutic target.
Citation Format: Govindi J. Samaranayake, Clara I. Troccoli, Mai Q. Huynh, Andrew Win, Debin Ji, Eric T. Kool, Priyamvada Rai. Towards a better understanding of MTH1 as a therapeutic target in RAS-driven cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5473. doi:10.1158/1538-7445.AM2017-5473
Abstract 5479: Redox stress as a therapeutic Achilles heel in castration-resistant prostate cancer
Authors: Troccoli Clara I. , Samaranayake Govindi J. , Huynh Mai Q. , Kage Karen , Kwon Deukwoo , Ban Yuguang , Chen Xi S. , Zarco Enrique R. , Jorda Merce , Burnstein Kerry L. , Rai Priyamvada 
Published: July 2017

Abstract
Androgen deprivation therapy (ADT) initially suppresses prostate cancer (PC) progression. However, castration resistant PC (CRPC) cells inevitably emerge, resulting in incurable disease. We recently demonstrated that AD produces a form of cellular senescence leading to outgrowth of CRPC subpopulations from the AD-sensitive parental cells. Gene expression profiling studies comparing the parental LNCaP line to the senescence-resistant, early CRPC variant, LNCaP SB5, revealed an enrichment of thiol-based redox-protective proteins in the latter under AD conditions. This finding suggests that redox stress due to hyperactivated mitogenic/survival signaling or metabolic stresses may be an important and understudied Achilles heel in the progression to CRPC. Here we present the effects of inhibiting thioredoxin-1 (TRX1), a redox-protective protein that was identified as being elevated in our early CRPC LNCaP SB5 model. Suppression of TRX1 expression via shRNA led to profound growth suppression of CRPC cells, relative to their AD-sensitive counterparts, and significantly reduced CRPC xenograft tumor growth. Furthermore, under AD, TRX1 suppression promoted p53-induced cell death, which was accompanied by increased reactive oxygen species (ROS). These in vitro and in vivo results were recapitulated using a Phase II clinical trial-tested chemical TRX1 inhibitor. Thus our results point to TRX1 as a critical requirement for CRPC progression and provide a rationale for using TRX1 inhibitors in conjunction with ADT to limit CRPC.
Citation Format: Clara I. Troccoli, Govindi J. Samaranayake, Mai Q. Huynh, Karen Kage, Deukwoo Kwon, Yuguang Ban, Xi S. Chen, Enrique R. Zarco, Merce Jorda, Kerry L. Burnstein, Priyamvada Rai. Redox stress as a therapeutic Achilles heel in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5479. doi:10.1158/1538-7445.AM2017-5479
Abstract 5480: Peroxiredoxin 2 mediates the survival of ECM-detached ovarian cancer cells
Authors: Davison-Versagli Calli A. 
Published: July 2017

Abstract
Non-tumorigenic epithelial cells require anchorage to the extracellular matrix (ECM) in order to survive; however, it has been recognized that metastatic cancer cells must have the ability to survive in anchorage independence. Approximately 70% of epithelial ovarian cancer (EOC) cases are diagnosed after EOC cells have already metastasized, making EOC more difficult to treat. EOC cells shed from the primary tumor and accumulate in ascites in the peritoneal cavity before attaching and forming secondary tumors throughout the peritoneal cavity. A better understanding of the molecular mechanisms involved in the survival of this non-adhesive subset of cells that survive in anchorage independence in the ascites could lead to the development of improved chemotherapeutics and thus resulting in better survival rates of EOC patients. Striking increases of reactive oxygen species (ROS) mediated by ECM-detachment has been shown to inhibit survival in non-tumorigenic mammary epithelial cells. Furthermore, previous publications from our laboratory suggest that the antioxidant enzymes catalase, superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2) are critical for metabolic maintenance and survival of ECM-detached breast cancer cells; however, many other antioxidant enzymes and their role in the survival of ECM-detached ovarian cancer cells have yet to be unveiled. Here, we have found that the antioxidant enzyme, Peroxiredoxin 2, is important in the survival of ECM-detached ovarian cancer cells, and elimination of this enzyme in SKOV3 cells results in decreased ability to survive in anchorage independence. Thus, our data reveal that Peroxiredoxin 2 may be an attractive target for the design of chemotherapeutics aimed at eliminating metastatic ovarian cancer cells. Given these data, we are working to understand the role of other members of the Peroxiredoxin family, namely Peroxiredoxin 1, in the survival of ovarian cancer cells in anchorage independence.
Citation Format: Calli A. Davison-Versagli. Peroxiredoxin 2 mediates the survival of ECM-detached ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5480. doi:10.1158/1538-7445.AM2017-5480
Abstract 5483: Investigating the role of the retinoblastoma protein in induction and maintenance of oncogene-induced cellular senescence in tumor suppression
Authors: Harajly Mohamad , Zalzali Hasan , Ghamloush Farah , Saab Raya H. 
Published: July 2017

Abstract
Oncogene-induced cellular senescence is a tumor suppressor response resulting in irreversible cell cycle exit, and is dependent on the p53 and RB pathways. Loss of p53 has recently been shown to allow re-entry of senescent cells into the cell cycle. The role of the RB1 protein in maintenance of the senescent state is less well studied. We investigated whether RB1 is necessary for the induction as well as the maintenance of oncogene-induced senescence, and we also evaluated whether RB1 activation is sufficient to induce and/or maintain senesce in the absence of a functional p53 pathway. Inactivation of RB1 prior to onset of senescence led to failure of senescence induction, with impaired cell cycle exit and failure to induce senescence markers. On the other hand, loss of RB1 after cells had already entered oncogene-induced senescence was able to reverse some features of the senescence phenotype, but did not result in successful cell division and accumulation. Interestingly, in the absence of p53, constitutively active RB1 was sufficient for cells to undergo oncogene-induced senescence, and effectively prevented colony formation. Finally, while p53 inactivation was sufficient for senescent cells to re-enter the cell cycle, constitutive activation of RB1 prevented cell cycle re-entry, even in the absence of p53. Our findings show that RB1 is necessary for both the induction and maintenance of oncogene-induced senescence, and that active RB is sufficient for senescence induction as well as its maintenance, both in the presence and absence of p53. These results have direct implications on targeting RB activation as a senescence-inducing approach in both p53 wild type and p53-defective premalignant and malignant tumors.
Note: This abstract was not presented at the meeting.
Citation Format: Mohamad Harajly, Hasan Zalzali, Farah Ghamloush, Raya H. Saab. Investigating the role of the retinoblastoma protein in induction and maintenance of oncogene-induced cellular senescence in tumor suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5483. doi:10.1158/1538-7445.AM2017-5483
Abstract 5485: The combined effects of polyamine and GSH inhibition on the viability of human cancer cell lines
Authors: Grady John , Holzer Davey , Keleher Kaci , Meetz Emma , Feirer Russ 
Published: July 2017

Abstract
Polyamines play essential roles in DNA stability and cell proliferation, making polyamine metabolism a potential target for cancer therapeutics. The spermine analog N1,N11- Diethylnorspermine (DenSpm) reduces levels of ODC, the enzyme responsible for polyamine biosynthesis, and also induces the enzyme SSAT, responsible for the catabolism of polyamines. Polyamines have been shown to inactivate reactive oxygen species (ROS), including peroxides, protecting mammalian cells from oxidative damage to nucleic acids. The catabolism of polyamines by SSAT, in contrast, leads to the production of ROS, which results in cellular death and limits the progression of cancer. Buthionine sulfoximine (BSO) selectively depletes stores of intracellular glutathione GSH, an antioxidant that neutralizes ROS. We hypothesized that treating cancer cell lines with both DenSpm and BSO will have a synergistic cytotoxic effect on the cells, due to the depletion of ROS-scavenging polyamines, the generation of ROS caused by DenSpm and the absence of GSH. Treatment of the four cell lines, MCF-7, MDA-MD-231, Caco-2 and PANC-1, with DenSpm resulted in moderate reductions in cell viability as measured using the Cell Titer Blue assay (Promega, Inc.). As has been widely reported in other mammalian systems, DenSpm (10 µM) reduced intracellular polyamine concentrations (HPLC of benzoylated polyamine derivatives) and induced SSAT (Western Blots). Treatment of cells with BSO (500 µM) caused a significant decrease in intracellular GSH levels. Similar findings have been reported in previous studies with human neuroblastoma lines (Anderson, et al. 1999). The combination of BSO and DenSpm had effects markedly greater than either compound alone. Pretreatment of cells with BSO (500 µM) for 24 hours with subsequent removal of BSO before DenSpm (10, 100, 1000 µM) addition resulted in significantly reduced viability in all cell lines. DenSpm was found to be most effective in the continued presence of BSO as compared to a 24-hour BSO pretreatment. The compounds used in combination also enhanced ROS production, further demonstrating their synergistic effects.
Citation Format: John Grady, Davey Holzer, Kaci Keleher, Emma Meetz, Russ Feirer. The combined effects of polyamine and GSH inhibition on the viability of human cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5485. doi:10.1158/1538-7445.AM2017-5485
Abstract 5486: Oxidative stress and selective protein carbonylation in human breast cancer tissue
Authors: Aryal Baikuntha P. , Rao Ashutosh 
Published: July 2017

Abstract
Protein carbonylation is an irreversible modification to the side chain of amino acid residues induced by severe oxidative stress. Reactive oxygen species (ROS) are constantly produced under normal as well as stress-induced conditions, and play a role in both cancer progression and cancer suppression. Tumor tissue are known to have higher ROS levels compared to surrounding healthy tissue but ROS-induced specific protein carbonylation and its unique role in cancer progression/suppression are poorly understood. In this study we compared the relative total and specific protein carbonylation in flash frozen human breast cancer and matched adjacent normal tissue using ELISA, two-color western blot, mass spectrometry, and immunoprecipitation approaches. To understand antioxidant capacity in tumor tissue, we analyzed superoxide dismutase (SOD) for its antioxidant activity and protein level. Our results indicate that tumor tissue has greater total protein carbonylation, lower SOD activity, lower SOD protein levels, and elevated levels of autophagy compared to matched adjacent healthy tissue. We also identified three specific proteins that showed higher level of carbonylation selectively in tumor tissue compared to adjacent normal tissue. Our findings were further confirmed using the immortalized MDA-MB-231 breast cancer cell line and MCF-12A noncancerous normal human epithelial breast cell. Identification of selectively carbonylated proteins in cancer tissue, and understanding their specific role in cancer progression may promote the development of targeted therapeutic approaches to mitigate or enhance oxidative damage of such proteins selectively in tumor tissue.
Citation Format: Baikuntha P. Aryal, Ashutosh Rao. Oxidative stress and selective protein carbonylation in human breast cancer tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5486. doi:10.1158/1538-7445.AM2017-5486
Abstract 5490: Non-overlapping promoter and super-enhancer-associated dependencies in multiple myeloma
Authors: Fulciniti Mariateresa , Lin Charles Y. , Samur Mehmet K. , Young Richard , Avet-loiseau Herve , Anderson Kenneth , Bradner James , Munshi Nikhil 
Published: July 2017

Abstract
The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well-defined. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators to identify their individual contribution to eventual functional effect in multiple myeloma (MM). To better understand how E2F1 and DP1 drive proliferation, we mapped the global occupancy of E2F1/DP1 in MM. Integration of E2F1 and DP1 genomic localization to MM reference epigenome revealed specific co-occupancy of the factors at promoters of active genes marked by H3K4me3, with a strong positive correlation between E2F and RNA Polymerase II (RNA Pol II) binding at transcription start sites. In contrast, active enhancers, as defined by promoter distal Mediator (MED1) peaks and marked by H3K27ac and BRD4, showed virtually no E2F binding. Unbiased hierarchical clustering revealed distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth/proliferation genes and BETs disproportionately at enhancer- regulated tissue specific genes confirming that these factors establish distinct target gene programs. At the extremes, we found less than 10% of genes were among the top 500 in BRD4 enhancer signal (i.e. SE-regulated) and top 500 E2F promoter signal. We hypothesized that the presence of BETs and E2F in distinct regulatory axes divides active genes in MM into those that can be selectively influenced by BET inhibition or E2F perturbation, but not both. In line with this we have observed that dual E2F and BET inhibition is synergistic for MM cell growth, both in vitro and in vivo. In conclusions, our results highlights the existence of distinct regulatory axes controlled by promoter and enhancer driven processes, suggesting a sequestered cellular functional control that may be perturbed in cancer with potential for development of a promising therapeutic strategy.
Citation Format: Mariateresa Fulciniti, Charles Y. Lin, Mehmet K. Samur, Richard Young, Herve Avet-loiseau, Kenneth Anderson, James Bradner, Nikhil Munshi. Non-overlapping promoter and super-enhancer-associated dependencies in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5490. doi:10.1158/1538-7445.AM2017-5490