bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2870: p28, a cell penetrating peptide fragment of azurin, inhibits COP1 mediated ubiquitination of wild type and mutated p53, but does not alter intracellular levels of c-jun
Authors: Yamada Tohru , Christov Konstantin , Shilkaitis Anne , Bratescu Laura , Green Albert , Santini Simona , Bizzarri Anna Rita , Cannistraro Salvatore , Gupta Tapas K. Das , Beattie Craig W. 
Published: August 2012

Abstract
Amino acids (aa) 50-77 of azurin, p28, a 128 aa member of the cupredoxin family of copper containing redox proteins, isolated from the opportunistic pathogen Pseudomonas aeruginosa is a cell penetrating peptide (CPP) that preferentially penetrates a wide variety of human cancer cells. Exposure of p53wt, mut cancer cells to p28 produces a post translational increase in the level of p53, inhibition of the cell cycle at G2/M and apoptosis (Yamada et. al., Mol. Can. Therap., 8:2947-58, 2009). Computer simulation (ClusPro, GROMACS) and domain specific antibodies to p53 suggest p28 binds to motifs that span aa 110–146 in flexible L1 loop and 80 and 276 of the p53 DNA binding domain (DBD), respectively. Western and RT-PCR analyses of human breast cancer, MCF-7 (p53wt), MCF-7 derived MDD2 (p53dom/neg), MDA-MB-231 (p53mut), and melanoma cells, Mel-29 (p53wt), Mel-23 (p53mut) and Mel-6 (p53null) exposed to p28 for 72 hrs showed a significant increase in the levels of p53 and p21 in MCF-7, MDA-MB-231, Mel-29 and Mel-23 cells, while significantly reducing the level of FoxM1 over a 72hr exposure. The level of STMN1 was not altered suggesting the block at G2/M does not involve microtubules. p28 significantly decreased the level of the E3 ligase COP1 in p53wt, mut MCF-7, MDA-MB-231, Mel-29 and Mel-23, but not in p53null Mel-6 cells. In addition, p28 did not significantly decrease the level of E3 ligases TOPORS, Pirh2 or HDM2 which also ubiquitinate p53. The levels of p53, p21, FoxM 1, STMN1, COP1, TOPORS and Pirh2 either remained essentially at control levels (p53, p21) or were elevated (FoxM1, STMN1, COP1, TOPORS, Pirh2) at some point during a 72 hr exposure of p53dom/neg MDD2 cells to p28. In contrast, COP1 has also been reported to negatively regulate cell proliferation in a c-jun-dependent manner and not regulate intracellular levels of p53 (Migliorini et. al., J. Clin. Invest., 121: 1329-43, 2011). The p28 induced decrease in the level of COP1 in p53wt, mut cancer cells was not accompanied by a sustained increase in c-jun, in any cancer cell line, suggesting that COP1 regulates the level of p53 in cancer cells independent of any effect on c-jun. These data also suggest that COP1, but not TOPORS or Pirh2, also binds within this region of p53, and that COP1 is a major regulator of p53 activity. In sum, these data suggest that p28 binds to a specific motif within the p53 DBD where it inhibits COP1 mediated binding to and ubiquitination of p53.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2870. doi:1538-7445.AM2012-2870
Abstract 2873: Opposing effects of NF-κB inhibition during chemical lung carcinogenesis
Authors: Zaynagetdinov Rinat , Karabela Sophia P. , Psallidas Ioannis , Sherrill Taylor P. , Kairi Chrysoula A. , Cheng Dong-Sheng , Vassiliou Spyridoula , Gleaves Linda A. , Han Wei , Zakynthinos Spyros G. , Yull Fiona E. , Roussos Charis , Kalomenidis Ioannis , Blackwell Timothy S. , Stathopoulos Georgios T. 
Published: August 2012

Abstract
Since recent evidence indicates a requirement for epithelial NF-κB signaling in lung tumorigenesis, we investigated the impact of the NF-κB inhibitor bortezomib on lung tumor promotion and growth. We used an experimental model in which wild-type mice or mice expressing an NF-κB reporter received intraperitoneal urethane (1 g/kg) followed by twice-weekly bortezomib (1 mg/kg) during distinct periods of tumor initiation/progression. Mice were serially assessed for lung NF-κB activation, inflammation, and carcinogenesis. Short-term proteasome inhibition with bortezomib did not impact tumor formation, but retarded the growth of established lung tumors in mice via effects on cell proliferation. In contrast, long-term treatment with bortezomib resulted in significantly increased lung tumor number and size. This tumor-promoting effect of prolonged bortezomib treatment was associated with perpetuation of urethane-induced inflammation and chronic up-regulation of interleukin-1α and proinflammatory C-X-C motif chemokine ligands (CXCL) 1 and 2 in the lungs. In addition to airway epithelium, bortezomib inhibited NF-κB in pulmonary macrophages in vivo, presenting a possible mechanism of tumor amplification. In this regard, RAW264.7 macrophages exposed to bortezomib showed increased expression of interleukin-1α, CXCL1, and CXCL2. In conclusion, although short-term bortezomib may exert some beneficial effects, prolonged NF-κB inhibition accelerates chemical lung carcinogenesis by perpetuating carcinogen-induced inflammation. Inhibition of NF-κB in pulmonary macrophages appears to play an important role in this adverse process.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2873. doi:1538-7445.AM2012-2873
Abstract 2875: Meta-iodo-benzylguanidine (MIBG) is a MYCN/MYC destabilizer that specifically targets neural crest derived tumors
Authors: Wang Stephanie , Maloney Nolan , Hsiao Ruth , Limpar Mariko , Ikegaki Naohiko , Tang Xao X. 
Published: August 2012

Abstract
Melanoma and malignant pheochromocytoma are known for high MYC expression. MYCN amplification and its over-expression are associated with the worst neuroblastoma disease outcome. Meta-iodo-benzylguanidine (MIBG) is a norepinephrine analogue and a mitochondrial respiration inhibitor. 131I-MIBG has been used for scintigraphic detection of neural crest derived tumors (neuroblastoma, pheochromocytoma and melanoma) that specifically uptake MIBG by norepinephrine transporters (NET). 131I-MIBG is also used for targeted radiotherapy of neuroblastoma and pheochromocytoma. Non-radiolabeled MIBG had been reported to be cytotoxic to neuroblastoma cells in vitro and in vivo. However, the molecular mechanism of its growth suppressive effect was not elucidated. Our previous studies showed that FCCP, a well-known mitochondrial respiration inhibitor, destabilized MYCN and MYC in neuroblastoma cells and caused growth suppression. In this study we confirmed that MIBG suppressed growth of neuroblastoma cell lines (SKNBE(2)C, IMR5, Nb69, and SKNAS), and its growth suppressive effect in each cell line correlated with NET expression in these cells. In addition, MIBG suppressed growth of neuroblastoma stem cells derived from SKNBE(2)C. MIBG treatment of SKNBE(2)C and SKNAS resulted in an increase expression of growth suppressive gene (GADD45B) and genes encoding for biomarkers of favorable neuroblastoma (CD44, EPHB6, EFNB2, EFNB3, NTRK1). Treatment of MYCN amplified (SKNBE(2)C, IMR5) and non-MYCN amplified (Nb69, SKNAS) neuroblastoma cells with MIBG resulted in marked reduction of MYCN and MYC expression, respectively in dose and time dependent fashions. Collectively, our studies suggest that MIBG not only targets neural crest derived tumors, but also is a MYCN/MYC destabilizing agent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2875. doi:1538-7445.AM2012-2875
Abstract 2885: Urokinase plasminogen activator system targeted delivery of arsenic trioxide loaded nanobins as a novel ovarian cancer therapeutic
Authors: Zhang Yilin , Swindell Elden P. , Ahn Richard W. , Mitra Anirban , Mazar Andrew P. , O'Halloran Thomas V. , Kenny Hilary A. , Lengyel Ernst 
Published: August 2012

Abstract
That the urokinase plasminogen activator receptor (uPAR) system is constitutively expressed in primary and metastatic ovarian cancer regardless of grade or stage, while it is only weakly expressed in normal tissues, identifies it as a possible therapeutic target. Taking advantage of the tumor-specific expression of uPAR, a nanoscale liposome (nanobin, NB) was coupled with an antibody (ATN 291) against the uPAR ligand, uPA, to facilitate receptor-mediated, targeted drug delivery. The nanobin was loaded with arsenic trioxide (As2O3, in short As), since our previous results had demonstrated effective tumor uptake and induction of tumor cell apoptosis using As loaded nanobins in an orthotropic model of human triple negative breast cancer. We hypothesized that the ATN 291-conjugated nanobin (NB-uPA Ab) would allow specific cellular internalization and increase the therapeutic index of As in ovarian cancer cells. Using flow cytometry and fluorescence microscopy, we measured the cellular uptake of NB(Calcein)-uPA antibody (Ab) in HeyA8, ovarian cancer cells. The data showed a dose-dependent pattern of internalization with maximum internalization at 24 hours. Furthermore, NB-uPA Ab showed elevated cellular uptake when compared to non-targeted NB. More importantly, delivery of the targeted nanobins is uPA/uPAR dependent. High doses of ATN-291 or scuPA inhibited the cellular binding of NB-uPA Ab to HeyA8 cells. Moreover, down-regulation of uPAR expression via RNA interference in ovarian cancer cells inhibited the cellular uptake of the NB-uPA Ab. The cell viability of HeyA8 cells was significantly reduced following treatment of both non-targeted NB(As) and NB(As)-uPA Ab when compared to empty NB treatment as determined by a cytotoxicity assay. However, the cytotoxicity of NB(As)-uPA Ab is 2.1-fold more potent than the non-targeted NB(As). Taken together, these data indicate that the uPA Ab conjugated nanobins improved drug delivery and enhanced the anti-cancer effects of As, demonstrating the utility of targeting the uPA/uPAR system in ovarian cancer chemotherapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2885. doi:1538-7445.AM2012-2885
Abstract 3013: Role of prostanoid signaling in lung cancer
Authors: Pamarthi Pavankumar , Savai Rajkumar , Pullamsetti Soni Savai , Seeger Werner , Grimminger Friedrich , Schermuly Ralph 
Published: August 2012

Abstract
RATIONALE: An increasingly large body of evidence indicates that PGE2 promotes tumor growth by stimulating EP4 receptor signalling with subsequent enhancement of cellular proliferation, metastasis and suppression of immune responses. However, the role of other EP receptors is not known. OBJECTIVE: We hypothesized that prostanoid receptors other than the EP4 receptor are involved in progression of Lung cancer. METHODS: We analyzed the expression profile of EP receptors in lung adenocarcinoma cell lines A549 and H1299 by using Real Time PCR, western blotting and immunofluorescence. All four EP receptors are getting expressed in both the cell lines. Both L-161982 (EP4 receptor specific antagonist) and SC-51322 (EP1 receptor specific antagonist) inhibited proliferation of both cell lines as assessed by thymidine incorporation assay. EP2 and EP3 receptors have not shown inhibitory affects in proliferation assays. SC-51322 has not decreased cAMP levels in A549 and decreased intracellular calcium levels. SC-51322 has inhibited pERK levels as shown in the western blots. In addition, SC-51322 inhibited migration of A549 cells in transwell migration assay. CONCLUSION: We conclude that EP1 receptor may play a role in lung cancer progression and metastasis. Finding out downstream molecules to EP1 receptor will give us a better understanding of this pathway in lung cancer and can provide therapeutic opportunities.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3013. doi:1538-7445.AM2012-3013
Abstract 3049: Development of novel survivin inhibitors to target mitotic machinery in cancers
Authors: Cooley James V. , Chettiar Somsundaram , Park In-Hee , Bhasin Deepak , Chakravarti Arnab , Kai Li Pui , Li Chenglong , Jacob Naduparambil K. 
Published: August 2012

Abstract
Survivin, a member of the inhibitor of apoptosis (IAP) protein family has essential roles in cell division and inhibition of apoptosis. Over-expression of survivin is observed in most human cancers, but survivin expression is not detectable in non-proliferating normal adult tissues. In dividing cells, survivin is detected as an integral component of the chromosomal passenger complex (CPC). In the CPC, survivin is organized as a homodimer, associated with Aurora B-kinase and plays a critical role in the recruitment of a number of proteins to the kinetochore and centromere, which are essential for mitotic progression. Several clinical correlative studies in cancer patients have shown that elevated levels of survivin decreases overall survival and leads to resistance to radiation and chemotherapeutic treatments. Thus, disruption of functional survivin along its dimer interface is hypothesized to inhibit the proliferation of cancer cells by further sensitizing them to therapeutic agents and radiation. Recently, through HTS-NMR and AS/MS affinity based screenings, compound 1 (C1) was identified to bind to the dimerization interface of survivin monomers. Further development of this compound was accomplished by computational modeling of inhibitor interactions along the dimerization interface, which has lead to the design of a panel of promising compounds analogous to compound 1. Two of the most potent inhibitors included LLP3 and LLP9, which showed significant levels of activity between 50 and 100 nM. In proliferating human umbilical vein endothelial cells (HUVEC) as well as in prostate cancer cells (PC3) cells, the compounds caused a delay in mitotic progression and major mitotic defects. These cells expressed physiological levels of GFP-tagged survivin, which were used for visualization in automated fluorescent time-lapse videomicroscopy to investigate how the survivin dimerization inhibitors affected cell cycle progression. The same microscopy methods were used for understanding the specificity and activity of each respective compound. The investigation of cells treated with each of the compounds allowed for resolution of subcellular level effects on mitotic progression and CPC organization/movement during mitosis. The qualitative microscopy data was enumerated in order to quantify effects the compounds had on cells. The cells were enumerated in triplicate and tracked for changes in their proliferation, cell death, changes in ploidy, and other mitotic defects. The relationships between structure and activity of the compounds will be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3049. doi:1538-7445.AM2012-3049
Abstract 3051: CDC28 protein kinase subunit 1B (CKS1B) is a potential therapeutic target in esophageal adenocarcinomas overexpressing the CDK inhibitor p21Cip1/Waf1
Authors: Ismail Amin , Bandla Santhoshi , Toia Liana , Godfrey Tony 
Published: August 2012

Abstract
Background: The incidence of adenocarcinoma of the esophagus and gastroesophageal junction (EAC) has grown faster than any tumor type in the United States and westernized countries, outpacing the next closest cancer by almost 3 times. This rising incidence of EAC is associated with the increasing prevalence of obesity and gastroesophageal reflux disease (GERD). Due to the limited effect of current chemotherapy for this cancer, the search for new therapeutic targets is disparately needed. Chromosomal amplification is one mechanism by which cancer cells acquire and maintain neoplastic phenotype and genes that are amplified and overexpressed may represent potential therapeutic targets. Methods: DNA and RNA from a cohort of 116 patients were analyzed using SNP and mRNA expression microarrays respectively. Gene amplification was explored for correlation with expression and patient survival. Results: 25% of tumors harbor amplification at chromosome 1q which is significantly associated with poor survival. Although the amplicon is non-focal spanning almost the entire arm of chromosome 1q, only a subset of amplified genes (including The CDC28 protein kinase subunit 1B, CKS1B) are significantly overexpressed. CKS1B is an auxiliary protein required for ubiquitination and cytosomal degradation of the CDK inhibitors p27Kip1 and p21Cip1/Waf1 by the SCFSKP2 E3 ubiquitin ligase complex. Both p27Kip1 and p21Cip1/Waf1 inhibits CDK2/Cyclin E complex during the G1/S cell cycle transition. The endogenous protein expression of p27Kip1 is low among EAC cell lines. However the expression of p21Cip1/Waf1 is differential being very high in a subset of cells and low or undetectable in others. Knocking down CKS1B by siRNA in six EAC cell lines results in accumulation of p27 Kip1 with little or no effect on p21Cip1/Waf1 expression. CKS1B knockdown inhibits monolayer cell proliferation only in cells with high endogenous expression of p21Cip1/Waf1. Conclusion: We suggest that the combined action of accumulation of p27 Kip1 and the endogenously highly expressed p21Cip1/Waf1 triggers the response to CKS1B knockdown in EAC cell lines. We thus propose the potential use of CKS1B as a novel therapeutic target in esophageal adenocarcinomas with high p21Cip1/Waf1 expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3051. doi:1538-7445.AM2012-3051
Abstract 3053: Identification of a novel cytoplasmic role for MTDH/AEG-1 in chemoresistance as a RNA binding protein
Authors: Meng Xiangbing , Zhu Danlin , Wang Xinjun , Yang Shujie , Zhang Yuping , Xiong Zhi , Leslie Kimberly K. 
Published: August 2012

Abstract
Overexpression of metadherin (MTDH/AEG-1) has been documented in many solid tumors and is implicated in metastasis and chemoresistance. MTDH has been detected at the plasma membrane as well as in the cytoplasm and nucleus, and the function of MTDH in these locales remains under investigation. In the nucleus, MTDH acts as a transcription co-factor to induce expression of chemoresistance-associated genes. However, MTDH is predominantly cytoplasmic in solid tumors, and this localization has been shown to correlate with poor prognosis. In this study, we used endometrial cancer cells as a model system to define a new role for MTDH in the cytoplasm. First, MTDH was primarily localized to the cytoplasm in endometrial cancer cells, and the N-terminal region of MTDH was required to maintain cytoplasmic localization. Depletion of cytoplasmic MTDH in endometrial cancer cells restored chemosensitivity to various DNA damaging agents including mitomycin C (MMC) and doxorubicin. Next, we identified novel binding partners for cytoplasmic MTDH, including ribosome protein RPL4, ribosome biogenesis-related protein NPM1, and a component of the RNA induced silencing complex SND1. Association of MTDH with these cytoplasmic proteins was disrupted by nuclease treatment, demonstrating that nucleic acid is required for the interaction of cytoplasmic MTDH with these RNA metabolism and processing proteins. Furthermore, RNA binding protein-chromatin IP (RIP-chIP) analysis demonstrated that MTDH interacted with multiple mRNAs, and treatment with the PI3K and mTOR dual inhibitor BEZ235 altered the pattern of mRNAs that associate with MTDH. Knockdown of MTDH promoted an increase in protein levels of some MTDH-associated mRNAs. Finally, increased stress granule formation was observed in MTDH knockdown cells in response to heat shock, suggesting that one mechanism by which MTDH promotes chemoresistance is prevention of stress granule formation. Taken together, our data identify MTDH as an active RNA binding protein in the cytoplasm of cancer cells. Our findings suggest that the RNA binding properties of cytoplasmic MTDH serve to regulate genes involved in the drug resistance and metastasis of tumors and highlight MTDH as an ideal target for future drug development. Acknowledgements: This work was supported by NIH Grant R01CA99908 to K.K.L., and in part by the Department of Obstetrics and Gynecology Research Development Fund, the Institutional Research Grant Number IRG-77-004-31 from the American Cancer Society to XM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3053. doi:1538-7445.AM2012-3053