bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1030: Loss of PHLPPs protects against colitis by inhibiting epithelial apoptosis through upregulating AKT activity
Authors: Wen Yang-an , Li Xin , Goretsky Tatiana , Barrett Terrence A. , Gao Tianyan 
Published: August 2015

Abstract
Background & Aims: PHLPP, a novel family of protein phosphatases, plays an important role in balancing cellular signaling pathways that control cell death and proliferation. Loss of PHLPP expression promotes colorectal cancer (CRC) tumorigenesis and progression. Intestine epithelial cells (IECs) apoptosis contributes to the development of inflammatory bowel disease (IBD), and patients with IBD are at increased risk for CRC. We investigated the functional importance of PHLPP in intestinal inflammation.
Methods: Both Phlpp1 and Phlpp2 genes were deleted in mice. The effect of PHLPP double knockout (DKO) on the development of acute colitis was examined in dextran sulfate sodium salt (DSS)-treated mice. Biochemical and histological analyses were conducted to determine the extent of tissue inflammation and colon epithelial cell apoptosis. The expression of PHLPP proteins was examined in DSS-treated mice and IBD patient samples.
Results: In ulcerative colitis and Crohn's disease patient samples, both PHLPP1 and PHLPP2 protein expression was markedly decreased in colitis tissues compared to that in uninvolved tissues. In mice, PHLPP expression was significantly reduced in colonic epithelial cells following induction of colitis by DSS. Mechanistically, the inflammation-induced downregulation of PHLPP was mediated through proteasome-dependent protein degradation. Compared with wild-type mice, PHLPP DKO mice were protected from colitis induced by the DSS treatment as demonstrated by lower histopathological scores, and this reduced susceptibility to colitis was associated with decreased apoptosis and increased Akt activity in colonic epithelial cells. Furthermore, epithelial organoids derived from colon and small intestine of PHLPP DKO mice are more resistant to inflammation-induced apoptosis upon Akt activation.
Conclusion: These results indicated that PHLPP contributes to the pathogenesis of colitis by controlling epithelial cell apoptosis. Downregulation of PHLPP at the onset of inflammation plays a role in protecting intestinal epithelial cell injury by inhibiting apoptosis. However, prolonged PHLPP-loss may promote colon cancer initiation in IBD patients.
Citation Format: Yang-an Wen, Xin Li, Tatiana Goretsky, Terrence A. Barrett, Tianyan Gao. Loss of PHLPPs protects against colitis by inhibiting epithelial apoptosis through upregulating AKT activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1030. doi:10.1158/1538-7445.AM2015-1030
Abstract 1031: Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by activated Src
Authors: Guy Stephanie , Magee Patrick , Geletu Mulu , Arulanandam Rozanne , Raptis Leda 
Published: August 2015

Abstract
The signal transducer and activator of transcription-3 (Stat3) plays an important role in cancer etiology. Following activation of a number of growth factor or cytokine receptors or expression of oncogenes such as vSrc, Stat3 is phosphorylated at tyr-705, dimerizes and migrates to the nucleus where it activates transcription from a number of genes involved in cell division and survival. We recently discovered a novel pathway of activation of Stat3: Engagement of cadherins such as cadherin-11 (cad11), a cell to cell adhesion protein known to be involved in metastasis, induces a dramatic increase in the levels of the Rac and Cdc42 small GTPases, and this leads to interleukin-6 transcription and Stat3 activation. Stat3 in turn, downregulates the p53 tumor suppressor and upregulates anti-apoptotic genes, thus offering a potent survival signal.
A large number of oncogenes such as activated Src-527 activate the E2F transcription factor family, which induce the expression of genes involved in cell division. However, at the same time E2F is a potent apoptosis inducer, hence the high demand of transformed cells for antiapoptotic signals. Since cad11 activates Stat3, a potent survival factor, we examined the effect of cad11 downregulation upon transformation of mouse Balb/c3T3 fibroblasts by vSrc. Forced expression of high levels of activated Src caused a dramatic reduction in cad11 levels. On the other hand, intermediate Src levels, which are the levels that are physiologically relevant, did allow cad11 expression, albeit at lower levels. Paradoxically, cells expressing high Src levels had actually lower Stat3 than cells expressing intermediate Src levels. This could be due to the observed downregulatory effect of Src upon cad11, and it demonstrates that cad11 is a more potent Stat3 activator than Src. Cad11 knockdown through shRNA expression in cells expressing intermediate Src levels, caused a dramatic reduction in Stat3 activity and induced apoptosis. That is, the residual amounts of cad11 present are sufficient to activate Stat3 and prevent apoptosis induced by the Src/E2F axis. Taken together, these findings indicate that cad11, despite its presumed structural role, and in addition to its known role in promoting metastasis, it is actually also necessary for full neoplastic transformation by the Src oncogene.
Citation Format: Stephanie Guy, Patrick Magee, Mulu Geletu, Rozanne Arulanandam, Leda Raptis. Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by activated Src. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1031. doi:10.1158/1538-7445.AM2015-1031
Abstract 1035: An angiogenic role of E-cadherin-positive exosomes in ovarian cancer
Authors: Tang Maggie K. S. , Wong Alice Sze Tsai 
Published: August 2015

Abstract
Angiogenesis, the induction of vasculature, is a vital step for metastasis. Loss of E-cadherin is a well-established marker for tumor metastasis. In ovarian cancer, a highly metastatic tumor that is rapidly lethal, we and others have previously shown the deregulated pattern of E-cadherin and its close association with tumor progression. Although E-cadherin is synthesized as a transmembrane molecule, it can be shed from the cell surface (sE-cad) which accounts for a rapid removal of functional E-cadherin. Here, in addition to ectodomain shedding, we show for the first time that sE-cad can be actively released from ovarian cancer cells in the form of exosomes. These sE-cad-positive exosomes play a critical role in angiogenesis which stimulated the migration, permeability, and tubulogenesis of human umbilical vein endothelial cells in vitro, and promoted functional neovascularization in vivo. In search of the underlying mechanisms by which sE-cad-positive exosomes might regulate angiogenic endothelial cells, which lack E-cadherin, we showed that a novel heterophilic crosstalk between sE-cad and VE-cadherin. Moreover, such angiogenic effect was mediated through activation of the phosphatidylinositol 3-kinase/Akt-beta-catenin signaling cascade. These results uncover a new angiogenic function for sE-cad and a novel paradigm for sE-cad production which may have potential clinical implications (This study was supported by RGC grant HKU781013).
Citation Format: Maggie K. S. Tang, Alice Sze Tsai Wong. An angiogenic role of E-cadherin-positive exosomes in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1035. doi:10.1158/1538-7445.AM2015-1035
Abstract 1038: Cell-based screening identifies gene expression signature correlated with sensitivity to PI3K-mTOR dual inhibitor BEZ235
Authors: Zhang Jing , Guo Sheng , Bao Zhengzheng , Shang Limei , Wen Xiao , Wery Jean-Pierre , Ning Jinying 
Published: August 2015

Abstract
The PI3K-mTOR pathway is one of the major signaling cascades that promote tumor growth and cell survival. Multiple inhibitors targeting this important axis are currently under clinical investigation for cancer treatment and some are under preclinical development. Here we examined the anti-proliferation activity of BEZ235, a PI3K and mTOR dual inhibitor, in 243 human cancer cell lines of different caner types. We identified 35 lines that are sensitive to the inhibitor with IC50 values less than 0,04uM and 57 insensitive lines with IC50 values more than 0.4uM. We compared gene expression of the two groups by Affymetrix U219 arrays. With a p-value cutoff set at 0.00001, we identified 14 genes that are differentially expressed. These genes include epithelial membrane glycoprotein EPCAM and serine threonine kinase 31 (STK31). Furthermore, the mutation status of tubulin tyrosine ligase TTL is significantly correlated with sensitivity to BEZ235. These results suggested a potential genomic signature that could be predictive of response to BEZ235 and provided information that may help selecting patients that are likely to receive clinical benefit.
Citation Format: Jing Zhang, Sheng Guo, Zhengzheng Bao, Limei Shang, Xiao Wen, Jean-Pierre Wery, Jinying Ning. Cell-based screening identifies gene expression signature correlated with sensitivity to PI3K-mTOR dual inhibitor BEZ235. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1038. doi:10.1158/1538-7445.AM2015-1038
Abstract 1043: Blocking constitutive aryl hydrocarbon receptor (AhR) signaling attenuates androgen receptor activity
Authors: Ghotbaddini Maryam , Hemphill Aaron , Powell Joann B. 
Published: August 2015

Abstract
PURPOSE: The aryl hydrocarbon receptor (AhR) is a member of the basic-helix-loop-helix family of transcription factors. AhR is widely known for regulating the transcription of drug metabolizing enzymes involved in the xenobiotic metabolism of carcinogens and therapeutic agents, such as cytochrome P450-1B1 (CYP1B1). Additionally, AhR has also been reported to interact with multiple signaling pathways during prostate development. Here we investigate the effect of sustained AhR signaling on androgen receptor function in prostate cancer cells. METHODS/RESULTS: Immunoblot analysis shows that AhR expression is increased in androgen independent (C4-2) prostate cancer cells when compared to androgen sensitive (LNCaP) cells. qRT-PCR studies revealed constitutive AhR signaling in C4-2 cells without the ligand induced activation required in LNCaP cells. A reduction of AhR activity by short RNA mediated silencing in C4-2 cells reduced expression of both AhR and androgen responsive genes. The decrease in androgen responsive genes correlates to a decrease in phosphorylated androgen receptor and androgen receptor expression in the nucleus. CONCLUSION: These data indicates that AhR is required to maintain hormone independent signaling by the androgen receptor in C4-2 cells. Collectively, these data provide evidence of a direct role for AhR in androgen independent signaling and provides insight into the molecular mechanisms responsible for sustained androgen receptor signaling in hormone refractory prostate cancer.
These studies were supported by the RCMI grant 2G12RR003062-22.
Citation Format: Maryam Ghotbaddini, Aaron Hemphill, Joann B. Powell. Blocking constitutive aryl hydrocarbon receptor (AhR) signaling attenuates androgen receptor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1043. doi:10.1158/1538-7445.AM2015-1043
Abstract 107: Critical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair
Authors: Hamamoto Ryuji , Sone Kenbun , Nakamura Yusuka 
Published: August 2015

Abstract
γ-H2AX, the serine 139-phosphorylated form of the histone protein H2AX, is a marker of activation of the DNA damage machinery and is often overexpressed in many malignancies. Although γ-H2AX deregulation in cancer has previously been reported, the relevant molecular functions during carcinogenesis as well as its relationship with other histone modifications are still largely unknown. In the present study, we found that the histone methyltransferase Suppressor of Variegation 3-9 Homolog 2 (SUV39H2) methylated lysine 134 on histone H2AX, which is located in a unique portion of H2AX among the histone H2A family. When lysine 134 of histone H2AX was substituted to alanine, the amount of γ-H2AX production was significantly abolished. We also found lower γ-H2AX activity after introduction of the double-strand breakage in Suv39h2-double null cells or when SUV39H2 was knocked down. Concordantly, tissue microarray analysis of clinical lung tissues demonstrated a significantly positive correlation between K134-methylated H2AX and γ-H2AX levels. Furthermore, introduction of K134-substituted histone H2AX enhanced radio- and chemo-sensitivity of cancer cells, implying a critical role of methylation on the regulation of γ-H2AX production and the DNA repair pathways in cancer cells. This is the first report describing the functions of methylation on histone H2AX and its important role in the regulation of γ-H2AX production in cancer.
Citation Format: Ryuji Hamamoto, Kenbun Sone, Yusuka Nakamura. Critical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 107. doi:10.1158/1538-7445.AM2015-107
Abstract 1080: Computational and biochemical discovery of RSK2 as a novel target for epigallocatechin gallate (EGCG)
Authors: Chen Hanyong , Yao Ke , Chang Xiaoyu , Shim Jung-Hyun , Kim Hong-Gyum , Malakhova Margarita , Kim Dong-Joon , Bode Ann M. , Dong Zigang 
Published: August 2015

Abstract
The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). Protein interaction with EGCG is a critical step mediating the effects of EGCG on the regulation of various key proteins involved in signal transduction. By using computational docking screening methods for protein identification, we identified a serine/threonine kinase, 90-kDa ribosomal S6 kinase (RSK2), as a novel molecular target of EGCG. RSK2 includes two kinase catalytic domains in the N-terminal (NTD) and the C-terminal (CTD) and its activation requires phosphorylation of both the NTD and CTD. The computer prediction was confirmed by an in vitro kinase assay in which EGCG inhibited RSK2 activity in a dose-dependent manner. Pull-down assay results showed that EGCG could bind with RSK2 at both kinase catalytic domains in vitro and ex vivo. Furthermore, results of an ATP competition assay and a computer-docking model showed that EGCG binds with RSK2 in an ATP-dependent manner. In RSK2+/+ and RSK2-/- murine embryonic fibroblasts, EGCG decreased viability only in the presence of RSK2. EGCG also suppressed epidermal growth factor-induced neoplastic cell transformation by inhibiting histone H3 Ser10 phosphorylation. Overall, these results indicate that EGCG is a novel natural compound for suppressing RSK2 kinase activity.
Citation Format: Hanyong Chen, Ke Yao, Xiaoyu Chang, Jung-Hyun Shim, Hong-Gyum Kim, Margarita Malakhova, Dong-Joon Kim, Ann M. Bode, Zigang Dong. Computational and biochemical discovery of RSK2 as a novel target for epigallocatechin gallate (EGCG). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1080. doi:10.1158/1538-7445.AM2015-1080
Abstract 1083: Expression of an estrogen-regulated variant transcript of the peroxisomal branched chain fatty acid oxidase, ACOX2, in breast cancer
Authors: Bjørklund Sunniva , Kristensen Vessela N. , Seiler Michael , Grenaker Alnaes Grethe I. , Ming Yao , Kerrigan John , Naume Bjørn , Sachidanandam Ravi , Bhanot Gyan , Børresen-Dale Anne-Lise , Ganesan Shridar 
Published: August 2015

Abstract
Alternate transcripts from a single gene locus greatly enhance the combinatorial flexibility of the human transcriptome. Different patterns of exon usage have been observed when comparing normal tissue to cancers, suggesting that variant transcripts may play a role in the tumor phenotype. In this study we show that an intronic start variant of ACOX2, peroxisomal Acyl-CoA oxidase 2 (ACOX2-i9), is expressed and translated into a 25kDa protein in HepG2 cells as well as in several breast cancer cell lines, where it is required for optimal cell proliferation. shRNA knock down of the ACOX2-i9 variant results in decreased cell viability as assessed by colony formation assay of T47D and MDA-MB 436 cells. Moreover, expression of ACOX2-i9 is estrogen regulated, being induced by estradiol and inhibited by tamoxifen in ER+ T47D and Mcf-7 cells, but not in the ER- MDA-MB 436 cell line. This variant transcript is present predominantly in breast tumors as assessed in our initial set of 53 breast cancers and further validated in 87 tumor/normal pairs from the TCGA Breast Cancer dataset. It is specifically enriched in ER+ breast cancers where it's expression is associated with improved outcome. These data identify variant ACOX2 as a potential novel therapeutic biomarker in ER+ breast cancer.
Citation Format: Sunniva Bjørklund, Vessela N. Kristensen, Michael Seiler, Grethe I. Grenaker Alnaes, Yao Ming, John Kerrigan, Bjørn Naume, Ravi Sachidanandam, Gyan Bhanot, Anne-Lise Børresen-Dale, Shridar Ganesan. Expression of an estrogen-regulated variant transcript of the peroxisomal branched chain fatty acid oxidase, ACOX2, in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1083. doi:10.1158/1538-7445.AM2015-1083
Abstract 1089: Dissecting the potential distinct role/s of the four RNA binding domains in a phosphoprotein nucleolin using bioinformatics tools
Authors: Steinberg Ruchama Chaya , Singh Shaneen , Saxena Anjana D. 
Published: August 2015

Abstract
Nucleolin is an abundant RNA binding protein within the nucleolus containing four copies of a consensus RNA-binding domain (RBD1-4). Two of these contiguous RNA-binding domains (RBD12) are sufficient to bind to a variety of RNAs (e.g. rRNA, mRNA, ncRNA) through their highly conserved RNP-1/2 motifs. Nucleolin controls gene expression either post-transcriptionally through mRNA stability or by post-translational regulation, targeting mRNAs with ARE (AU-rich elements), NRE (nucleolin recognition elements) and/or G-rich regions. Nucleolin's RNA binding functions are directly implicated in various pathological conditions e.g. Alzheimer's disease, cancer and viral infection. Interestingly, nucleolin RNA binding properties and phosphorylation pattern change during the cellular response to stress suggesting possible collaboration in regulating gene expression. However, most RNA binding properties of nucleolin studied to date exclude its highly acidic N-terminus phosphorylation domain. Importantly, NMR structures are only available for RBD12 although RBD1-4 of nucleolin is required to interact with the evolutionary conserved motif (ECM) on pre-RNAs, which have important role/s in RNA processing. Our work in accordance with others has shown that the N-terminus domain plays a vital role in cell proliferation and therefore has potential to influence RNA-binding properties of nucleolin to regulate gene expression. Here we use bioinformatics tools to elucidate the RNA binding functions of all four RBDs of nucleolin individually and in various combinations. Using I-TASSER, a tertiary structure prediction algorithm, and the available structural data for RBD12, we first predicted models for RBD3 and 4.These models displayed nearly perfect superimposition of RBD34 with RBD12 where RBD3/2 and RBD4/1 align. Our central hypothesis is that nucleolin RBD3/4 domains can replace RBD1/2 domains in binding to RNAs. To test our hypothesis we have generated a variety of theoretical constructs of RBD1-4 with mutations in the RNP1/2 conserved sites of individual RBDs. We present the computational analyses of these constructs to predict the role/s of RBD3/4. We further predict any role/s imparted by N-terminus phosphorylation and/or the C-terminus GAR (Gly-Arg rich) domains in regulating RNA binding by nucleolin. This bioinformatics-based knowledge will provide useful insights about nucleolin-RNA interactions that can be framed into rationally designed experiments.
Citation Format: Ruchama Chaya Steinberg, Shaneen Singh, Anjana D. Saxena. Dissecting the potential distinct role/s of the four RNA binding domains in a phosphoprotein nucleolin using bioinformatics tools. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1089. doi:10.1158/1538-7445.AM2015-1089