bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1968: Obesity-induced activation of the androgen receptor
Authors: Siddiqui Faryal A. 
Published: August 2014

Abstract
Background: Prostate cancer is the second leading cause of cancer deaths for men in the US. Obesity increases the risk of dying from prostate cancer by almost 50%. The mechanisms by which obesity promotes a more aggressive disease remain largely unknown, hindering the development of effective approaches for improving patient outcome. It is hypothesized that because obesity is associated with elevated circulating levels of growth factors, activation of the androgen receptor may be responsible for the increased risk of a more aggressive cancer in obese men. This current study investigates the effects of obese sera on androgen receptor activity in a highly novel prostate cancer cell line.
Methods: LNCaP prostate cancer cells were stably infected with a lentiviral Dual-Luciferase reporter plasmid containing an androgen receptor response element (ARE). These stable ARE-reporter cells were then exposed to sera from either obese or control weight mice. Specific signal transduction inhibitors were used to determine the role of growth factor signaling in mediating the effects observed in response to exposure to the different sera.
Results: Exposure to obese sera activated the androgen receptor to levels three-fold greater than those seen with control sera. Intriguingly, use of a PI3 kinase inhibitor reduced obesity-induced activation of the AR by 75%, but only by 64% in the control sera. Studies are on-going to determine the role of both the Akt and MAPK pathways in these results, as well as the relative contribution of circulating androgens in activating the AR. Downstream targets of the AR induced by exposure to the obese sera are being identified both by Western blot and microarray analyses.
Conclusions: These results suggest that obesity-related circulating factors induce activation of the androgen receptor in prostate cancer cells. This activation appears to be both ligand dependent (androgens) and ligand independent (growth factors). These data suggest that one mechanism by which obesity influences time to progression and hormone independence is through activation of the androgen receptor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1968. doi:10.1158/1538-7445.AM2011-1968
Abstract 1969: Mapping the cross talk between parathyroid hormone related protein (PTHrP) and Integrins α6 and β4 in prostate cancer cells
Authors: Bhatia Vandanajay , Mula Ramanjaneya V. , Falzon Miriam A. 
Published: August 2014

Abstract
Prostate carcinoma is a leading cause of cancer deaths in men in the United States. An estimated 217,730 new cases and 32,050 deaths from prostate cancer have been reported in 2010 by the National Cancer Institute. For a cancer cell to become malignant it must adopt mechanisms to escape and survive outside its original environment, thus avoiding apoptosis. Parathyroid hormone-related protein (PTHrP) is among the many factors that contribute to this pro-survival state. The mechanisms through which PTHrP affects cell malignancy are not well understood.
Our previous studies have shown that PTHrP increases cell-surface levels of integrin α6β4 in prostate cancer cells. Over-expression of integrin α6β4 correlates with increased tumor invasion and metastasis. Integrin α6β4 also acts as a signaling molecule that activates anti-apoptotic phosphoinositide 3-kinase (PI3K) signaling pathways. The mechanism through which PTHrP increases α6 and β4 integrins levels is not clear.
We report that in PTHrP over-expressing prostate cancer cell lines (C4-2 and PC-3), the activity of α6 and β4 promoters is increased by ∼ 2.5 fold. We have also found increased NF-κB promoter activity in C4-2 and PC-3 cell lines as a result of PTHrP over-expression. Identification of elements within the integrin α6 and β4 gene promoters that are regulated by PTHrP signaling can provide valuable information regarding the mechanism of the PTHrP action in cancer cell survival and invasion. PTHrP also regulates α6 and β4 protein levels via a post-translational pathway, since the PTHrP protein half-life is higher in PTHrP-over expressing cells in comparison to empty vector control cells. This effect is mediated via the proteasome pathway, as ubiquitinated α6 and β4 levels are reduced in PTHrP over-expressing cells. Our future goals are to map the regulatory elements like NF-κB in the α6 and β4 integrin promoters that are regulated by PTHrP, and to identify the pathways via which PTHrP regulates the proteasome pathway. This might help understand the mechanism through which PTHrP acts in prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1969. doi:10.1158/1538-7445.AM2011-1969
Abstract 1976: Systematic identification of protein-protein interactions by Proximity Ligation Assay
Authors: Chen Tzu-Chi , Lin Kuan-Ting , Kuo Yu-Lun , Lee Pei-Ying , Chen Chun-Houh , Liu Yu-Wen , Huang Chi-Ying 
Published: August 2014

Abstract
Signal transduction pathways at cellular level require massive protein-protein interactions (PPIs) in response to different environmental cues. Diverse experimental techniques for detecting PPIs have been developed; however, the large amount of data accumulated from various sources has posed a grand challenge in data reliability for PPI. To evaluate the role of PPIs within signaling pathways, we have systematic profiled PPI residing in 28 KEGG pathways, for example mTOR, MAPK, Wnt, VEGF, and Hedgehog, and 3 cancer-related pathways stored in KEGG (http://www.genome.jp/kegg/). Of ∼60000 human PPI collected, 2786 PPI can be detected within targeted 14 pathways. To validate these PPIs, we used a newly developed Proximity Ligation Assay, which detects endogenous PPI through a pair of antibodies that bind to proteins in close proximity. Each PPI can be made visible through DNA amplification and quantified by counting fluorescent dots in the cell. Of 1,204 PPIs examined, 557 PPIs can be confirmed in HeLa cells. Specifically, 383 out of 557 validated PPIs residing within pathways in cancer and mTOR, Wnt and MAPK pathways are considered novel “links” based on annotations of KEGG. Moreover, 79 validated PPIs are cross-talk events among 35 signaling transduction and cancer related pathways. Surprisingly, only 16 PPIs (out of 557 confirmed PPIs) are highly correlated in 7 sets of cancer cells from NCI60 microarray dataset. In this large scale PPI profiling, 41 apoptosis related PPIs were further tested in 3 cancer cell lines to explore the possibility for drug screening. These systematic analyses of endogenous PPI pairs within and between pathways may set the foundation to disrupt the signaling pathways by targeting PPIs in cancer drug discovery.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1976. doi:10.1158/1538-7445.AM2011-1976
Abstract 198: TRAF2 phosphorylation is essential for cancer-cell adaptation to chronic cellular stress
Authors: Habelhah Hasem , Blackwell Ken , Zhang Laiqun 
Published: August 2014

Abstract
The tumor microenvironment is known to trigger chronic endoplasmic reticulum (ER) and oxidative stresses, and cancer-cell adaptation to such chronic stresses has profound consequences for malignant progression and the response to therapy. TRAF2 regulates cellular response to TNFα, ER and oxidative stresses by activating the JNK/c-Jun and IKK/NF-κB signaling cascades. We mapped two phosphorylation sites (Ser-11 and Ser-55) on the N-terminal RING domain of TRAF2, and reported that phosphorylation at these sites increases basal and TNFα-induced NF-κB activation. Recently, we identified TBK1 and PKCζ as the kinases that directly phosphorylate TRAF2 at Ser-11 and Ser-55 sites, respectively. We found that in addition to TNFα, ER and oxidative stresses also strongly induce TRAF2 phosphorylation at both sites. This dual phosphorylation of TRAF2 promoted IKK activation and inhibited the prolonged phase of JNK activation in response to ER and oxidative stresses. Importantly, TRAF2 phosphorylation was found to be essential for cancer-cell survival under conditions of chronic cellular stress. Specifically, the endogenous TRAF2-dockdown cancer cells that were stable expressed with phospho-null-mutant TRAF2 (TRAF2-S11/55A) did not survive under conditions of chronic ER and oxidative stresses, while their TRAF2-WT counterparts survived under the same conditions. In addition, the TRAF2-S11/55A-expressing cancer cells formed significantly smaller tumors in vivo and exhibited greater sensitivity to anti-cancer drug-induced apoptosis than did TRAF2-WT-expressing counterparts. Functional assays revealed that TRAF2 phosphorylation not only promotes NF-κB-dependent gene expression, but also suppresses JNK-mediated degradation of Bcl-2 and cIAP1 at post-transcriptional level in the context of ER and oxidative stresses. Collectively, these findings suggest that TRAF2 phosphorylation plays a critical role in tumor progression by promoting the expression of anti-apoptotic proteins in cancer cells, and could be a new target for anti-cancer drug development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 198. doi:10.1158/1538-7445.AM2011-198
Abstract 1982: TGF-beta induced SIK cooperates with Smurf2 to negatively regulate type I receptor kinase signaling
Authors: Vanlandewijck Michael , Lönn Peter , Kowanetz Marcin , Kowanetz Katarzyna , Bush Christer , Heldin Carl-Henrik , Moustakas Aristidis 
Published: August 2014

Abstract
Signal transduction pathways, like transforming growth factor beta (TGFβ), regulate many physiological processes and require control mechanisms to safeguard proper and timely action. Dysregulation of TGFβ signaling is established as a major player in cancer progression. We have recently described how negative regulation of TGFβ signaling is controlled by the serine/threonine kinase salt-inducible kinase (SIK). SIK is induced by TGFβ and forms protein complexes with the TGFβ type I receptor and with the inhibitory Smad7, which leads to type I receptor downregulation. We now investigate this mechanism further and demonstrate similarities between TGFβ/Smad-mediated immediate-early induction of SIK and Smad7. We also relate another protein of the negative feedback loop of TGFβ signaling, the E3 ubiquitin ligase Smurf2, to this mechanism of regulation. We provide evidence that Smurf2 cooperates with SIK to downregulate the type I receptor. Both the kinase activity of SIK and the ubiquitin ligase activity of Smurf2 are important for proper receptor turnover. However, Smurf2 does not directly bind to SIK, but participates in the complex via the PY-motif of Smad7. We thus establish a central role for Smad7 during SIK-mediated receptor downregulation. Finally, we explore the role of SIK in a cancer context by investigating its expression profile in human prostate cancer tissues. In conclusion, we have uncovered a phosphorylation/ubiquitination-dependent mechanism for TGFβ receptor downregulation that could play important roles during cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1982. doi:10.1158/1538-7445.AM2011-1982
Abstract 1985: The activation of GSK3 by HGF-MET axis is responsible for differentiation of rhabdomyosarcoma cells
Authors: Miekus Katarzyna , Bobela Wojciech , Majka Marcin 
Published: August 2014

Abstract
Introduction: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma among children. At the late stages (metastatic) the outcome for the patients is very poor. The molecular basis for loss of cell differentiation in the process of carcinogenesis is not well understood. Differentiation status of rhabdomyosarcoma cells strongly influences its progression and metastatic ability and therefore the overall patient survival.
At the onset of myogenic differentiation MET receptor is rapidly downregulated and on the other hand the activation of MET receptor in rhabdomyosarcoma has been shown to influence proliferation, survival and migration.
Aim: Dissecting the role of HGF-MET receptor axis and GSK3 activation in the process of RMS differentiation.
Materials and methods: Cell lines used in experiments: RH30 (ARMS), SMS-CTR (ERMS). Real time RT-PCR and western blotting were used to evaluate gene expression and the activation of various intracellular signaling pathways, respectively. The evaluation of protein activation in RMS cell lines was performed after stimulation with HGF.
Results: We found that, during differentiation process the expression of MyoD, characteristic for poorly differentiated rhabdomyosarcoma cells decreased and the expression of myogenin, protein characteristic for differentiated/ matured muscle cells increased. That was paralleled by decreased expression of MET receptor. In RMS cell lines with stable downregulation of MET receptor the expression of differentiation related genes was similar to differentiated RMS cells. When we study the activation of GSK3 we observed the phosphorylation of GSK3 beta on serine 9 after HGF stimulation. The intracellular pathway responsible for GSK3 beta phosphorylation turn out to be PI3K-AKT dependent. We observed also the accumulation of beta-catenin in the nucleus of RMS cells stimulated with HGF. This effect was father augmented when HGF was used together with BIO, small molecular inhibitor of GSK3 beta.
Conclusion and future directions: In this study we have shown that the expression and signaling of MET receptor is responsible for differentiation of RMS cells. Moreover we postulate that MET receptor exerts its influence on RMS cells differentiation through GSK3 beta activation. These findings might have the significant clinical implication for the treatment of RMS cells because they suggest that induction of differentiation of RMS cells by blocking MET receptor could inhibit growth of RMS tumors. Finally, we think that also GSK3 beta could be used as the new therapeutic target to induce differentiation of RMS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1985. doi:10.1158/1538-7445.AM2011-1985
Abstract 1987: Identification and characterization of novel Notch3 interacting proteins in ovarian cancer
Authors: Stoeck Alexander , Chen Xu , Shih Ie-Ming , Wang Tian-Li 
Published: August 2014

Abstract
Ovarian serous carcinoma (OSC) represents one of the most aggressive neoplastic diseases because most cases present at an advanced stage when therapy is usually ineffective. We have previously reported that Notch3 gene amplification and overexpression occurs frequently in OSC. Activation of Notch3 signaling is essential for the survival of OSC cells with Notch3 overexpression, especially in the presence of chemotherapeutic agents. Notch3 pathway activation has been known to transcriptionally regulate an array of genes, including those involved in stem cell biology and oncogenesis in OSC. The current study aims at identifying the binding proteins of Notch-ICD in OSC cells using recombinant human Notch3-ICD protein and protein interaction arrays.
We have identified several novel Notch3-ICD interacting proteins. Among them, we focused on characterizing WW domain containing E3 ubiquitin protein ligase 2 (WWP2), a member of the NEDD4 family of ubiquitin-protein ligases. We found that WWP2 specifically co-immunoprecipitated with Notch3-ICD but not with Notch1-ICD, and ubiquitinated Notch3-ICD, leading to its degradation in lysosomes. Overexpression of WWP2 in OVCAR3 cells reduced Notch3 steady state protein levels, suppressed Notch3 reporter activity, and inhibited cellular proliferation. On the other hand, a dominant negative isoform of WWP2, as well as knockdown WWP2 using shRNAs, prevented ubiqutination of Notch3-ICD, increased Notch3-ICD protein levels, and enhanced Notch3 reporter gene activity. Compared to their normal counterparts, including fallopian tube and ovarian surface epithelial cells, OSC cell lines and tissues had a significantly lower mRNA and protein levels of WWP2 while Notch3 protein expression was inversely correlated with WWP2 expression levels. The above results provide new evidence that WWP2 protein is a key regulator of Notch3-ICD protein expression levels in ovarian cancer cells. WWP2 modulates Notch3 signaling activity by regulating its degradation pathway and downregulation of WWP2 may represent a novel mechanism to activate the Notch3 signaling pathway in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1987. doi:10.1158/1538-7445.AM2011-1987
Abstract 1990: GNMT activates mTOR/Raptor signaling and delays G2/M progression through interacting with DEPTOR
Authors: Yen Chia-hung , Lu Yao-Cheng , Li Chung-Hsien , Lee Cheng-Ming , Chen Chia-Yen , Cheng Ming-Yuan , Huang Shiu-Feng , Lee Yan-Hwa Wu , Chen Yi-Ming A. 
Published: August 2014

Abstract
GNMT is a tumor suppressor for hepatocellular carcinoma (HCC). We found that DEPTOR, a novel mTOR binding protein, interacts with GNMT through its PDZ domain. DEPTOR expression is significantly increased in HCC, especially among patients with HCV infection. Loss of DEPTOR in HuH-7 cells activates S6K but reduces Akt activation and cell growth. DEPTOR overexpression activates Akt and extends survival of HCC cells. Overexpression of GNMT counteracts DEPTOR induced Akt activation and activates mTORC1 downstream signaling via disruption of the DEPTOR-mTOR interaction. Moreover, GNMT overexpression delays G2/M progression, which causes senescence and slows proliferation of HuH-7 cells, sensitizing them to rapamycin. We suggest that GNMT by interacting with DEPTOR regulates the cellular homeostasis of hepatocytes through modulation of Akt/mTORC1 signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1990. doi:10.1158/1538-7445.AM2011-1990
Abstract 1993: Interaction between histone demethylase and deacetylase may mediate activity of HDAC inhibitors in human breast cancer cells
Authors: Huang Yi , Vasilatos Shauna N. , Boric Lamia , Shaw Patrick G. , Davidson Nancy E. 
Published: August 2014

Abstract
Histone acetylation and methylation are two important epigenetic entities that interact with each other in chromatin remodeling and gene transcription regulation. It has been shown that abnormal activities of histone lysine deacetylases (HDACs) and histone lysine demethylases (KDMs) are associated with aberrant gene expression in cancer development. However, the precise molecular mechanisms underlying the crosstalk between HDACs and KDMs are still elusive. In this study, we showed that exposure of human breast cancer MDA-MB-231 and MDA-MB-468 cells to inhibitors against the zinc cofactor dependent class I or II HDACs, but not NAD+ dependent class III HDAC, led to significant increases of global di or mono-methylation of histone 3 lysine 4 (H3K4me2/me1) which are specific substrates of histone lysine-specific demethylase 1 (LSD1) and key positive chromatin marks promoting transcriptional activation. HDAC inhibitors did not affect in vitro demethylation activity of recombinant LSD1 and did not alter the nuclear presence of the LSD-CoREST-HDAC1/2 complex, indicating the inhibition of LSD1 activity in breast cancer cells by specific HDAC inhibitors likely occurs through disrupting the functional interaction between LSD1 and HDACs rather than direct competition with enzymatic substrate at the active site of LSD1 or suppression of LSD1 protein levels. Inhibition of LSD1 activity by its inhibitor, pargyline, or RNAi in MDA-MB-231 cells caused an increase in acetylation of H3K9 (AcH3K9), suggesting that LSD1 is an important regulator of HDAC activity in breast cancer. Chromatin immunoprecipitation (ChIP) demonstrated that LSD1/HDAC repressive complex is recruited to the promoter of one candidate target gene, estrogen receptor alpha (ERα), in ER negative breast cancer cells and the reactivation of silenced ERα by HDAC inhibitor is associated with increased H3K4me2, acetylH3K9 and acetylH4K16 at ERα promoter. In addition, combined treatment with HDAC inhibitors and the LSD1 inhibitor, pargyline, resulted in enhanced levels of H3K4me2 and AcH3K9, and synergistic growth inhibition of MDA-MB-231 cells. These data suggest a crosstalk between the histone demethylase, LSD1, and histone deacetylases as a novel regulatory mechanism in mediating activity of HDAC inhibitors and may help in designing combinations that could have significant clinical translation in breast cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1993. doi:10.1158/1538-7445.AM2011-1993