bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2248: The implication of STAT3 degradation and its mitochondrial functions in cellular senescence
Authors: Igelmann Sebastian , Deschênes-Simard Xavier , Lessard Frédéric , Bourdeau Véronique , Ferbeyre Gerardo 
Published: May 2015

Abstract
Cellular senescence is a stable growth arrest of the cell cycle considered to be a mechanism of tumor suppression. We have recently described a senescence associated protein degradation or SAPD process that targets many proteins required for tumor progression. The Signal transducer and activator of transcription 3 is one of the targets of SAPD and its downregualtion by RNAi is sufficient to trigger senescence. In the last decade several different functions of STAT3 have been described. Beyond its canonical role as a transcription factor, it has been shown that STAT3 is imported into mitochondria and regulate the activity of the respiratory chain. In this study we want to clarify which function of STAT3 is required to prevent senescence. To do that we have made several mutants of STAT3 affecting different domains of the protein and tested their ability to rescue the senescence response to an anti-Stat3 shRNA. We have found that phosphorylation on residue S727 of STAT3 is important to reestablish proliferation in shSTAT3 induced senescence. Further, transcriptional activity of STAT3 is not required to rescue senescence as a mutant unable to enter the nucleus or the transcriptionally death STAT3 K180A are both able to bypass shSTAT3-induced senescence. Moreover, phosphorylation on Y705 seems not to be important as Y705F STAT3 is also able to reestablish proliferation. All in all, it seems that mitochondrial function of STAT3 is required to prevent senescence since STAT3 S727 phosphorylation is linked to the mitochondrial import of STAT3.
Citation Format: Sebastian Igelmann, Xavier Deschênes-Simard, Frédéric Lessard, Véronique Bourdeau, Gerardo Ferbeyre. The implication of STAT3 degradation and its mitochondrial functions in cellular senescence. [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 2248. doi:10.1158/1538-7445.AM2014-2248
Abstract 225: Overexpression of truncated Ron augments benzyl isothiocyanate-induced apoptosis in human breast cancer cells
Authors: Sehrawat Anuradha , Singh Shivendra V. 
Published: May 2015

Abstract
Phytochemicals from edible plants remain attractive for prevention of breast cancer, which is a leading cause of cancer-related mortality in women worldwide. We have shown previously that benzyl isothiocyanate (BITC), a small-molecule found in edible cruciferous vegetables such as garden cress, confers significant protection against mammary cancer development in MMTV-neu transgenic mice. BITC-mediated prevention of mammary carcinogenesis in MMTV-neu mice in vivo is associated with tumor cell apoptosis induction and elimination of breast cancer stem cells (bCSC). In cultured human breast cancer cells, BITC-induced apoptosis is accompanied by activation of multidomain proapoptotic protein Bax whereas inhibition of bCSC self-renewal is significantly attenuated by overexpression of truncated Ron (recepteur d’origine nantais) tyrosine kinase. Ron expression is very low in normal human breast epithelium but its overexpression has been reported in about 50% of primary breast cancers. In addition, mammary-specific overexpression of wild-type Ron as well as its constitutively active form induces highly metastatic breast tumors in mice. The present study was undertaken to study the role of truncated Ron (sfRon) in BITC-induced apoptosis using MCF-7 and MDA-MB-361 human breast cancer cells. Overexpression of sfRon resulted in statistically significant augmentation of BITC-induced apoptotic cell death in both cell lines as judged by flow cytometry after staining with Annexin V and propidium iodide, analysis of histone associated DNA fragment release into the cytosol, and/or cell proliferation assay. On the other hand, sfRon overexpressing MCF-7 cells were resistant to BITC-mediated G2/M phase cell cycle arrest when compared with parental cells. Increased apoptosis following BITC treatment in sfRon overexpressing cells was due to enhanced activation of Bax and/or Bak. Taken together, these findings indicate that overexpression of sfRon sensitizes human breast cancer cells to BITC-induced apoptosis. This investigation was supported by the NCI grant CA129347-06.
Citation Format: Anuradha Sehrawat, Shivendra V. Singh. Overexpression of truncated Ron augments benzyl isothiocyanate-induced apoptosis in human 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 225. doi:10.1158/1538-7445.AM2014-225
Abstract 2250: Role of single strand binding protein 1 in TERT recruitment to telomeres and in maintaining telomere G-overhangs
Authors: Pandita Tej K. , Pandita Raj 
Published: May 2015

Abstract
Telomeres cap the ends of all eukaryotic chromosomes from degradation or end-to-end fusions. Mammalian telomeres are maintained by telomerase which is a ribonucleoprotein complex that includes a reverse transcriptase catalytic unit called TERT and a functional telomerase RNA (TR or TERC), which acts as a template to maintain telomere length. Telomerase maintains telomere length, by overcoming incomplete lagging strand synthesis known as the “end replication problem” during DNA replication. Mammalian stem and cancer cells utilize telomerase to extend telomeric G-overhangs to partially (stem cells) or completely (tumor cells) maintain telomere ends. Cells expressing telomerase also have higher levels of single strand binding 1 (SSB1) protein, which has a known critical role in the DNA damage responses and double strand break repair specifically by homologous recombination. We have established that SSB1 binds specifically to G-strand telomeric DNA in vitro, and associates in vivo with telomeres both in human and mouse cell lines. Interestingly, SSB1 interacts with the TERT protein, and determines the amount of TERT interaction with telomeres. Deletion/depletion of SSB1 reduces TERT interaction with telomeres and leads to G-overhang loss, but has no effect on in vitro telomerase activity. We will discuss, how SSB1 is required for telomerase recruitment to telomeres to facilitate G-strand DNA extension and to maintain telomeres.
Citation Format: Tej K. Pandita, Raj Pandita. Role of single strand binding protein 1 in TERT recruitment to telomeres and in maintaining telomere G-overhangs. [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 2250. doi:10.1158/1538-7445.AM2014-2250
Abstract 2256: p53 gene expression is epigenetically regulated during replicative senescence in keratinocytes
Authors: Kim Reuben H. , Kang Mo K. , Kim Terresa , Yang Paul , Hong Christine , Shin Ki-Hyuk , Park No-Hee 
Published: May 2015

Abstract
Cancer is one of the most prevalent age-associated diseases in elderly populations and is largely attributed to accumulation of genetic mutations secondary to the loss of tumor suppressive functions. p53 is a potent tumor suppressor that is implicated in organismal aging in vivo and replicative senescence in vitro; however, its transcriptional regulation during replicative senescence in cells remain unclear. The current study was undertaken to examine the epigenetic regulation of p53 transcription during replicative senescence in normal human keratinocytes. Normal human oral keratinocytes (NHOKs) undergoing senescence upon serial subcultures exhibited a decrease in p53 gene expression. Methylation status of two CpG islands in the p53 promoter was evaluated by treating with 5-aza-CdR, a demethylating agent, and by using bisulfite methylation sequencing analysis. Status of histone modification was evaluated using Chromatin Immunoprecipitation (ChIP) assay with anti-H3K27me3, a repressive mark, and anti-H3Ac, an active mark at the 5 different sites of the p53 promoter regions. In the presence of 5-aza-CdR, there was no increase in p53 expression in senescent NHOK at both mRNA and protein level. Bisulfite-sequencing analysis revealed no methylation changes at the CpG islands in the p53 promoters from young and senescent NHOK. However, during replicative senescence in NHOK, there were notable enrichment of anti-H3K27me3 occupancy and significant decrease in anti-H3Ac occupancy in the p53 promoter regions, indicating that chromatin at the p53 locus undergo compaction during replicative senescence. Our study demonstrates that the diminution of p53 during replicative senescence is epigenetically regulated in human keratinocytes.
Citation Format: Reuben H. Kim, Mo K. Kang, Terresa Kim, Paul Yang, Christine Hong, Ki-Hyuk Shin, No-Hee Park. p53 gene expression is epigenetically regulated during replicative senescence in keratinocytes. [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 2256. doi:10.1158/1538-7445.AM2014-2256
Abstract 226: Chemopreventive potential of curcumin in prostate cancer
Authors: Ide Hisamitsu , Lu Yan , Yamaguchi Raizo , Muto Satoru , Horie Shigeo 
Published: May 2015

Abstract
Curcumin contains multiple active compounds that have potent anti-inflammatory and anti-cancer properties. The present study investigates the molecular mechanisms of curcumin in the prostate cancer models. Treatment of LNCaP and 22Rv-1 prostate cancer cells with curcumin inhibited the cell proliferation. Genome-wide expression profiling, using oligonucleotide microarrays, revealed genes differentially expressed with curcumin treatment in prostate cancer cells. We identified one of the up-regulated genes, Aldo-Keto reductase 1C-2(AKR1C-2) which is involved in testosterone metabolism. Quantitative PCR confirmed significant up-regulation of AKR-1C2. The suppression of tumor growth is associated with the inhibition of expression of androgen receptor and androgen metabolism through AKR1C2 leading the induction of cell death by apoptosis. These results suggest that curcumin natural bioactive compounds could have potent anti-cancer property and the regulation of both androgen and androgen receptor. These pathways could exert pleiotrophic effects in prevention and treatment of prostate cancer.
Citation Format: Hisamitsu Ide, Yan Lu, Raizo Yamaguchi, Satoru Muto, Shigeo Horie. Chemopreventive potential of curcumin in prostate 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 226. doi:10.1158/1538-7445.AM2014-226
Abstract 2260: c-Myc induced senescence is dependent on transactivation of actin depolymerizing factor (ADF)/cofilin to mediate potent bystander effect
Authors: Lin Shih-Ting , Tsai Cheng-Han , Lee Yi-Jang , Lo Chia-Chien , Chou Yen-Ting 
Published: May 2015

Abstract
Oncogene-induced senescence may prevent unlimited proliferation and lead to cell death. This phenomenon is likely to be associated with up-regulation of p53 and p16INK4 tumor suppressor. Morphological transformation is also an important feature of senescence that exhibits enlarged cell volume and flat morphology. In this study, we found that c-Myc was co-upregulated with cofilin-1, an actin-binding protein essential for actin dynamics and morphological maintenance in replicative senescence. Additionally, oxidative stress induced senescent phenotypes also accompanied by up-regulation of both c-myc and cofilin-1. Knockdown of cofilin-1 was sufficient to minimize the cell shapes and senescence associated β-galactosidase marker that was induced by over-expressed c-myc or oxidative stress. Over-expression of cofilin-1 was also sufficient to induce senescence in the absence of p53 and p16INK4, but was unable to influence c-Myc level. On the other hand, over-expression of c-Myc could induce cofilin-1 expression. We next found that c-myc was able to induce the transactivation of cofilin-1 gene according to results of quantitative polymerase chain reaction (qPCR) and luciferase reporter gene assay. Furthermore, the results of ChIP assay provided evidence that c-myc can bind to two proximal E-box elements nearby the transcriptional initiation on cofilin-1 gene promoter. Although c-myc promoted cellular senescence in vitro, the conditional medium from c-myc over-expressing A549 cells accelerated migration and proliferation in separate cultured cells without c-myc over-expression. Knockdown of cofilin-1 also alleviated this bystander effect caused by over-expression of c-myc. Therefore, c-myc oncogene may require cofilin-1 for cell senescence that influences the growth of other tumor cells. Taken together, current data provide evidence that c-myc/cofilin-1 signaling pathway is a novel mechanism on promoting oncogene-induced cellular senescence and tumor progression.
Citation Format: Shih-Ting Lin, Cheng-Han Tsai, Yi-Jang Lee, Chia-Chien Lo, Yen-Ting Chou. c-Myc induced senescence is dependent on transactivation of actin depolymerizing factor (ADF)/cofilin to mediate potent bystander effect. [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 2260. doi:10.1158/1538-7445.AM2014-2260
Abstract 2265: Sub-fractions of conditioned medium, from hypoxia-induced cells with multipotent potential, exhibit a significant anti-oncogenic activity
Authors: Pinney Emmett , Montes-Camacho Mayra , Brintle Kayler , Posch Christian , Menen Rhiana , Easter David , Bouvet Michael , Hoffman Robert , Naughton Gail 
Published: May 2015

Abstract
We have previously shown that a human soluble cell conditioned media (CCM) from hypoxia-induced, potentially multipotent cells, grown in a perfusion bioreactor system inhibits tumor cell growth in vitro and in two animal models. Here we present data that indicate that a low molecular weight sub-fraction from the CCM has an increased anti-oncogenic activity. This activity was demonstrated in orthotopic pancreatic models, nRAS melanoma assays and over 10 additional human cancer cell lines in vitro. In an orthotopic BxPC3 pancreatic cancer model, there was a statistically significant improvement in survival following weekly intravenous injections of 0.1ml of sub fractioned CCM, as well as a significant improvement with 0.5ml intraperitoneal injections post-resection, as measured by Kaplan Meier analysis (p&lt;0.05) (figures below). Uveal and nRAS melanoma cancer cell growth was inhibited by greater than 90% in in-vitro proliferation assays. The mechanism of action of the CCM is the induction of apoptosis through the upregulation of Caspase 3 and 9, as demonstrated by immunostaining of Annexin V and immunoblot ayalysis. In a Miapaca nude mouse daily dose study, tumor mass and metastatic extent was substantially reduced in treated mouse versus the control. Further, in a BXPC3 nude mouse daily dose study, 60% (p&lt;0.05) of treated mice were tumor free after four weeks of treatment, while only 10% were tumor free in the control group . Little or no apparent drug toxicity was observed. These results indicate that the CCM sub-fraction could be a useful raw material for a treatment for a large range of neoplastic diseases.
Citation Format: Emmett Pinney, Mayra Montes-Camacho, Kayler Brintle, Christian Posch, Rhiana Menen, David Easter, Michael Bouvet, Robert Hoffman, Gail Naughton. Sub-fractions of conditioned medium, from hypoxia-induced cells with multipotent potential, exhibit a significant anti-oncogenic activity. [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 2265. doi:10.1158/1538-7445.AM2014-2265
Abstract 2269: Combination of erlotinib and epigallocatechin-3-gallate induces apoptosis of squamous cell carcinoma of the head and neck through posttranslational regulation of Bim and Bcl-2
Authors: Haque Abedul , Rahman Mohammad A. , Chen Zhuo G. , Shin Dong M. , Amin A.R.M. Ruhul 
Published: May 2015

Abstract
Purpose: Effective chemopreventive strategies could save millions of lives. We have previously reported that the combination of the EGFR-TKI erlotinib and the green tea constituent epigallocatechin-3-gallate (EGCG) exhibited synergistic chemopreventive effects in head and neck cancers by inducing the expression of Bim, p21, p27, and inhibiting the phosphorylation of ERK and AKT and expression of Bcl-2. In the current study, we further investigated the mechanism of regulation of Bim, Bcl-2, p21 and p27, and their role in apoptosis.
Methods: Well characterized and genetically validated squamous cell carcinoma of the head and neck cell lines were used throughout the study. Annexin V staining was conducted for apoptosis assay. Expression of mRNAs and proteins were measured by RT-PCR and Western blotting, respectively. Gene overexpression and knockdown strategies were used to activate or shut down the expression of specific proteins.
Results: siRNA-mediated silencing of Bim significantly inhibited apoptosis induced by the combination of erlotinib and EGCG (p=). On the other hand, overexpression of Bcl-2 significantly protected cells from apoptosis (p=), whereas overexpression of constitutively AKT had minimal effect on apoptosis (actual values). Analysis of mRNA expression by RT-PCR revealed that neither erlotinib, EGCG nor their combination had any significant effects on the mRNA expression of Bim, p21, p27 or Bcl-2, suggesting post-transcriptional regulation of Bim, p21, p27 and Bcl-2 by the combination of erlotinib and EGCG. Furthermore, we found that erlotinib or the combination of EGCG and erlotinib inhibited the phosphorylation of Bim, and that inhibition of protein translation by cycloheximide pretreatment stabilized Bim, suggesting posttranslational regulation of Bim.
Conclusion: Our results strongly suggest that the combination of erlotinib and EGCG induces apoptosis of SCCHN cells by regulating Bim and Bcl-2 at the post-translational level. Currently, a clinical trial is underway at Winship Cancer Institute of Emory University to inhibit or reverse the progression of oral premalignant lesions using this combination. (This study is supported by R03CA159369, P50CA128613 and Robbins Scholar Award of Winship Cancer Institute).
Citation Format: Abedul Haque, Mohammad A. Rahman, Zhuo G. Chen, Dong M. Shin, A.R.M. Ruhul Amin. Combination of erlotinib and epigallocatechin-3-gallate induces apoptosis of squamous cell carcinoma of the head and neck through posttranslational regulation of Bim and Bcl-2. [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 2269. doi:10.1158/1538-7445.AM2014-2269
Abstract 2272: Understanding resistance to Trail and Trail agonists
Authors: Chen Hong , Carrasco Rosa A. , Feng Hui , Hollingsworth Robert E. , Xiao Zhan , Tice David A. 
Published: May 2015

Abstract
Trail and Trail agonists induce apoptotic cell death in cancer cells while sparing normal cells making them promising drug candidates. However, Trail and Trail agonists tested so far in clinical trials have had disappointing results. We hypothesize that one reason for the lack of success could be resistance to Trail receptor agonism. In order to understand the underling mechanisms, we set out to generate a panel of Trail resistant models. Following weeks of continuous treatment with Trail, resistant cells began to emerge. Interestingly, no cross resistance to other cytotoxic agents such as doxorubicin, taxol and camptothecin was observed in the Trail receptor agonist resistant cells suggesting that the resistance mechanisms were specific to the extrinsic cell death pathway. We examined a series of factors such as ligand binding, surface receptor levels and caspase cascade activation. Here we highlight two specific mechanisms observed in a colorectal cell line DLD1 and a pancreatic cancer cell line PSN1. In both resistant models, the activation of the intrinsic and extrinsic caspase cascades were severely diminished starting at caspase-8. In the PSN1 model, TRAILR2 surface expression is significantly suppressed. Reduction of TRAILR2 by siRNA in the parental PSN1 cells also resulted in significant reduction of Trail receptor agonist activity in contrast to what was observed in the parental DLD1 cells. On the other hand, expression of caspase-8 proenzyme was severely attenuated in the DLD1 resistant cells. There was no significant change of caspase-8 mRNA expression found in resistant DLD1 suggesting post-translational control. Together, we conclude that Trail resistance is mainly due to early extrinsic pathway blockage such as down regulation of caspase-8 and TRAILR2.
Citation Format: Hong Chen, Rosa A. Carrasco, Hui Feng, Robert E. Hollingsworth, Zhan Xiao, David A. Tice. Understanding resistance to Trail and Trail 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 2272. doi:10.1158/1538-7445.AM2014-2272
Abstract 2274: RIP1-mediated sensitivity to SN38 induced by TNF in colon adenocarcinoma cell lines
Authors: Cabal-Hierro Lucia , O'Dwyer Peter J. 
Published: May 2015

Abstract
BACKGROUND: TNF is a dual role cytokine involved both in cell death and survival that is expressed in the tumor microenvironment. However, little is known about the molecular events that mark the biological outcomes of such opposite biological events. Recently, the protein kinase RIP1 has been identified as a new intermediate involved in the responses activated after DNA damage induction.
PURPOSE: In this study we investigated how TNF modulates the sensitivity to SN38 in colon cancer cell lines. We focused further on HT29- and HCT116-derived cell lines in which RIP1 or RIP3 proteins expression were stably downregulated.
RESULTS: We found that TNF increases cellular sensitivity to different chemotherapeutic drugs under both normoxic and hypoxic conditions over a panel of different colon adenocarcinoma cell lines. Combinations with SN38 were highly synergistic. In HT29 and HCT116 cell lines (TNF resistant and TNF sensitive respectively), we analyzed this interaction by studying P-H2-AX induction, cell proliferation (clonogenic assays and BrdU incorporation) and cell cycle distribution. To study the role of RIP1 and RIP3 on the biological responses triggered by SN38, HT29- and HCT116-derived cell lines expressing low levels of RIP1 and RIP3 were analyzed. While knockdown of RIP3 had no effect on SN38 cytotoxicity, RIP1 down regulation produced a 2.5-fold increased resistance to SN38 under hypoxic conditions. This change in SN38 sensitivity also correlated with a reduction in the levels of P-H2-AX in the presence of TNF, suggesting dependence of DNA damage induction by SN38 on RIP1.
CONCLUSIONS: These data suggest that RIP1 may be a key intermediate in determining cell death following SN38 treatment. Additional studies in tumor samples are in progress.
Citation Format: Lucia Cabal-Hierro, Peter J. O'Dwyer. RIP1-mediated sensitivity to SN38 induced by TNF in colon adenocarcinoma cell lines. [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 2274. doi:10.1158/1538-7445.AM2014-2274