bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 504: First in vitro radiobiological characterizations of cells from chordoma origin
Authors: Kato Takamitsu , Tsuda Akihisa , Fujimori Akira , Kamada Tadashi , Tsujii Hirohiko , Okayasu Ryuichi 
Published: February 2011

Abstract
Although chordoma, a rare bone cancer, has been treated with surgery and/or radiation including heavy ions, few in vitro characterizations of chordoma cells are available. The main reason for this is the extremely long doubling time associated with the only recognized cell line, U-CH1. Here, we derived a cell line (designated as U-CH1-N) from U-CH1 and made the in vitro characterization possible, and results with U-CH1-N were compared with those with HeLa (cervical cancer) and U87-MG (glioblastoma) cells. The cell doubling times for HeLa, U87-MG and U-CH1-N were 18 h, 24 h and 3 days respectively. U-CH1-N had the most DNA content among the three, was near tetraploid, and showed an abnormal karyotype. U-CH1-N and U87-MG were more sensitive to x-irradiation than HeLa cells. Heavy ion irradiation more efficiently killed all three cell lines than x-rays did. Relative biological effectiveness (RBE) at 10% survival for U87-MG and HeLa cells was about 2.5 for 70keV/μm carbon ions and 3 for 200keV/μm iron ions, while for U-CH1-N it was 2.5 for carbon and 4 for iron ions. Four different chemical agents producing various DNA lesions were used for further characterization of these cells. Although camptothecin, mitomycin C or cisplatin did not reveal strong cytotoxity to U-CH1-N compared with other cells, bleomycin, which produces DNA strand breaks, showed marked cytotoxic effect on U-CH1-N. Our data provide the first chronological cell survival information using cells of chordoma origin and also help explain the successful chordoma treatment by heavy ions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 504.
Abstract 5041: Aspirin acetylates and activates p53 in HT-29 and HCT-116 colon cancer cells
Authors: Alfonso Lloyd F. , Chivukula Raghavender , Marimuthu Srinivasan , Gunaje Jayarama B. 
Published: February 2011

Abstract
Increasing evidences from human epidemiological studies, animal models and in vitro experiments suggest that regular use of aspirin may reduce the risk of cancer of the colon; however, the mechanisms are not well understood. Since aspirin's protective effect is mainly observed in epithelial cell types which are more resistant to chemotherapy, an urgent need exists to identify the primary targets and cancer preventive pathways affected by aspirin. We hypothesized that aspirin's anti-cancer effect may involve acetylation of the tumor suppressor protein p53 and modulation of target gene expression. In the present study, we demonstrate that exposure of HT-29 and HCT-116 colon cancer cells to aspirin caused acetylation of p53 at lysine 382 (K382). HT-29 cells harbor a mutant form of p53 (R273H), whereas HCT-116 contain wild type p53. Acetylated p53 was mainly localized to the nucleus. In both cell types aspirin induced acetylation of p53 in a concentration dependent manner, and this was associated with increased p53 DNA binding activity. Consistent with this, we also observed induction of p21, a protein involved in cell cycle arrest as well as Bax, a mitochondrial proapoptotic protein. Aspirin also caused acetylation of bacterially expressed recombinant p53 in vitro, suggesting that it is a non-enzymatic reaction. Our observation that aspirin acetylates p53 leading to induction of target gene expression suggest that its anti-cancer effect may involve activation of the p53 pathway. Since p53 is mutated in nearly 50% of all tumors which leads to loss of its function, our observation also suggests that aspirin may find use in chemotherapy to reactivate mutant p53.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5041.
Abstract 5047: Synergistic anti-cancer activity of the CDK4/6 inhibitor PD-0332991 in combination with 5-fluorouracil-based chemotherapy in human colon cancer cells
Authors: Pishvaian Michael J. , Yang Shaoxian , Zouhairi Majed El , Wu Christina S. , Mishra Lopa , Avantaggiati Maria-Laura 
Published: February 2011

Abstract
Background: The cell cycle activator cyclin-dependent kinase 4 (CDK4) is overexpressed in many cancers and is a promising target for novel anti-cancer therapies. PD-0332991 (Pfizer, Inc) is a highly specific CDK4/6 inhibitor that has proven anti-cancer efficacy in multiple pre-clinical models, and is currently undergoing Phase II clinical testing in humans. PD-0332991 inhibits tumor cell growth by inducing cell cycle arrest. Sequential therapy with PD-0332991 followed by DNA damaging cytotoxic chemotherapy could produce additive or synergistic anti-cancer effects. Our goal was to assess the anti-tumor efficacy of a combination of PD-0332991 and cytotoxic chemotherapy in vitro, and in vivo. We also sought to determine the mechanisms of anti-cancer activity seen with combination therapy.
Methods: First, using human colorectal cancer (CRC) cell lines, we performed in vitro cell growth assays to determine the effects of a combination of PD-0332991 and 5-fluorouracil (5-FU) or oxaliplatin. Next, we tested the activity of PD-0332991, oral capecitabine (an oral 5-FU prodrug), or both in mice bearing human CRC xenografts. Finally, we assessed the mechanisms of cell death in vitro and in resected xenograft tumor samples.
Results: The combination of PD-0332991 and 5-FU or oxaliplatin exhibited additive/synergistic anti-cancer activity, in vitro. Furthermore, synergistic anti-cancer activity was observed in mice bearing xenografts of HCT 116 human CRC cells upon treatment with a combination of PD-0332991 and capecitabine. Virtually no anti-tumor activity was observed in mice treated with PD-0332991 or capecitabine alone. In assessing the mechanism of anti-tumor activity, in vitro and in resected xenograft samples, no increase in apoptosis was observed, as determined by annexin V and TUNEL staining. Even when cells were synchronized in G1 with PD-0332991 and then released and treated with 5-FU or oxaliplatin, there was no increase in apoptosis. Thus, assessment of alternative mechanisms of cell death, including cell senescence and autophagy are ongoing.
Conclusions: Our results demonstrate an additive/synergistic anti-tumor activity with the combination of PD-0332991 and traditional cytotoxic chemotherapy. The mechanisms of anti-tumor activity have yet to be determined, but are not dependent upon apoptosis. Given the synergistic anti-tumor activity, these results suggest that a clinical trial of PD-0332991 and 5-FU-based chemotherapy is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5047.
Abstract 5057: The insulin-like growth factor receptor I promotes motility and invasion of bladder cancer cells through Akt- and MAPK-dependent activation of paxillin
Authors: Metalli David , Lovat Francesca , Tripodi Farida , Xu Shi-Qiong , Alberghina Lilia , Vanoni Marco , Baffa Raffaele , Iozzo Renato V. , Gomella Leonard G. , Morrione Andrea 
Published: February 2011

Abstract
The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. Aberrant IGF-IR signaling is implicated in several types of tumors, including carcinomas of the lung, breast, prostate, pancreas, liver and colon. However, whether the IGF-IR contributes to the transforming phenotype of urothelial cells has not been clearly established but recent data suggest that the IGF-IR is over-expressed in bladder cancer.
In this study we demonstrated by immunohistochemical analysis that the IGF-IR is over-expressed in invasive bladder cancer (T3/T4) tissues compared to non-malignant controls. We have also characterized the mechanism of action of the IGF-IR in cancer urothelial cells using urothelial carcinoma-derived 5637 and T24 cells. Although activation of the IGF-IR did not appreciably affect their growth, it did promote migration and stimulate in vitro wound closure and invasion through extracellular matrix. These effects required the activation of the Akt and MAPK pathways and IGF-I induced Akt- and MAPK-dependent phosphorylation of paxillin, which relocated at dynamic focal adhesions at the protruding edge of migrating urothelial cancer cells. Using siRNA strategies we also demonstrated that paxillin was necessary for promoting IGF-I-mediated motility and invasion in bladder cancer cells.
In conclusion, our results provide the first evidence for a role of the IGF-IR in motility and invasion of bladder cancer cells, and support the hypothesis that the IGF-IR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. The IGF-IR could represent a novel molecular target in bladder cancer and could also serve as a novel tumor biomarker for diagnosis and possibly prognosis of bladder tumors.
This work has been supported by the Benjamin Perkins Bladder Cancer Fund, the Martin Greitzer Fund and National Institutes of Health Grants RO1 DK068419 (A.M.) and RO1 CA39481 and RO1 CA047282 (R.V.I.).
§Present address: Medimmune, One Medimmune Way, Gaithersburg, MD 20878
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5057.
Abstract 5060: Downregulation of THAP11 by Bcr-Abl promotes CML cell proliferation through c-Myc expression
Authors: Yokota Daisuke , Nakamura Satoki , Takemura Tomonari , Hirano Isao , Ono Takaaki , Shigeno Kazuyuki , Fujisawa Shinya , Takeshita Kaori , Misawa Kiyoshi , Ohnishi Kazunori 
Published: February 2011

Abstract
[Background and Purpose] THAP11 (thanatos-associated protein 11) is one of the zinc-dependent, sequence-specific DNA-binding factors, which regulate cell proliferation, apoptosis and cell cycle. It has been reported that THAP11 is ubiquitously expressed in normal tissues and frequently downregulated in several tumors. In CML cells, we found that THAP11 expression was inhibited. We investigated the mechanisms of the suppression of THAP11 and its function in CML cell proliferation. [Methods] The cells used in this study were human CML cell lines, K562 and Meg01 cells. Primary CML cells were obtained from the bone marrow of CML (CP) patients. Human normal mononuclear cells (MNCs) were isolated from bone marrow of healthy volunteers after obtaining informed consents. For analysis of THAP11 mRNA expression, quantitative RT-PCR was performed in all cell lines treated with Abl kinase inhibitors (STI571, AMN107, and BMS354825). For proliferation analysis and the expression of c-Myc in CML cells, MTT assays, western blot and cell cycle analysis were performed in all cell lines transfected with Bcr-Abl siRNA, THAP11 siRNA, or THAP11 cDNA respectively. Moreover, THAP11 expression, c-Myc expression, and the colony counts of CFU-GEMM, CFU-GM, and BFU-E were analyzed in CML stem/progenitor cells transfected with Bcr-Abl siRNA or treated with Abl kinase inhibitors. [Results] In CML cell lines treated with Abl kinase inhibitors or transfected with Bcr-Abl siRNA, the expressions of THAP11 and c-Myc mRNA and protein were significantly increased compared to untreated cells. On the other hand, in CML cells transfected with the THAP11 cDNA, the c-Myc expression was suppressed. The overexpression of THAP11 induced G1 cell cycle arrest through p27 and p21 accumulation, and inhibited the CML cell proliferation. Moreover, in CML stem/progenitor cells obtained from patients with CML, the transfection with Bcr-Abl siRNA or treatment with Abl kinase inhibitors increased the expression of THAP11 mRNA and protein, and decreased the c-Myc expression and the counts of CFU-GEMM, CFU-GM and BFU-E. [Conclusion] Our results demonstrated that the Bcr-Abl suppressed the expression of THAP11, the depletion of THAP11 induced c-Myc expression, and induced the proliferation of CML cells through cell cycle progression. Moreover, induction of THAP11 expression inhibited the proliferation of CML stem/progenitor cells.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5060.
Abstract 5064: The non-receptor tyrosine kinase Fer is required for activated ErbB2-mediated tumorigenesis
Authors: Sangrar Waheed , Shi Changnian , Gao Yan , Greer Peter A. 
Published: February 2011

Abstract
The fer proto-onogene encodes a non-receptor protein-tyrosine kinase (PTK) which together with the parologous Fps/Fes kinase makes up a distinct F-BAR domain containing subclass of PTKs. F-BARs have recently been shown to mediate membrane binding and bending properties that confer roles in receptor endocytosis and vesicle trafficking. Among known substrates of the Fer PTK are cortactin and F-BAR/SH3 containing adaptor proteins that regulate cytoskeletal remodeling and membrane dynamics important to cellular functions such as polarity determination, migration and mitogenesis. Mice deficient in Fer, Fps/Fes or both kinases are overtly healthy; although they do display enhanced responses to endotoxin challenges. Biochemical studies have implicated Fer in growth factor signaling, cadherin-dependent cell-cell adhesion, integrin-mediated adhesion and redox signaling. Cell biological studies have suggested a role for Fer in potentiating proliferation and migration. Recent results in our laboratory have provided compelling biological proof-in-principle that Fer is required for mammary tumorigenesis. RNAi-based knockdown of Fer reduced the tumorigenesis of the metastatic MDA-MB-231 breast cancer cells in mouse xenografting studies. In addition, tumor development in a transgenic mouse model of Her2/Neu/ErbB2-mediated breast tumorigenesis was significantly delayed in Fer-deficient mice by virtue of a targeted knock-in kinase-inactivating mutation in the mouse fer locus. Biochemical internalization assays suggested that EGFR endocytosis was enhanced in Fer-deficient tumor-derived epithelial cell cultures. These data point to a tumor promoting function for Fer in mammary tumorigenesis through a mechanism involving prolongation of ErbB2 signaling. Taken together, these studies suggest that pharmacological intervention of Fer may have therapeutic benefit in human ErbB2 positive breast cancer and potentially, in other epithelial cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5064.
Abstract 5084: Treadmill exercise modulates AMP-activated protein kinase and downstream signaling in mammary gland of p53+/−, but not p53+/+ mice
Authors: Wheatley Karrie E. , Nogueira Leticia M. , Perkins Susan N. , Hursting Stephen D. 
Published: February 2011

Abstract
Epidemiological data show that exercise is generally protective against breast cancer. Inhibition of mammalian target of rapamyocin (mTOR) through activation of AMP-activated protein kinase (AMPK) has been shown to be responsive to exercise. Decreased activation of ribosomal protein S6, a marker for mTOR inhibition, is associated with decreased growth and proliferation. Recently, this energy-sensing pathway has been shown to be inhibited by increased production of reactive oxygen species (ROS) leading to AMPK activation. ROS levels are maintained by p53-inducible anti-oxidant enzymes. Therefore, we hypothesized that energy sensing pathways that mediate the protective effects of exercise in breast cancer are modulated by p53 gene dosage. To test this hypothesis, we fed ovariectomized mice a high-fat diet (60% kcal) ad libitum for 10 weeks to model post-menopausal obesity. Mice were then randomized to a sedentary or exercise regimen (n=15/group). Exercised mice ran on a variable speed treadmill (5% incline, 20 m/min, 40 min/day, 5 days/week for 22 weeks). Changes in percent body fat were measured every 2 weeks using quantitative magnetic resonance. Immunoblot analysis was performed to measure phosphorylation of AMPK (Thr 172) and ribosomal protein S6 (Ser 240/244) relative to total levels in the mammary fat pad (MFP). Also, qRT-PCR was performed to measure mRNA expression of the p53-inducible anti-oxidant enzyme sestrin 1. At the end of the diet-induced obesity regimen, there was no effect of p53 genotype on percent body fat (54.4 ± 0.7 in p53+/+ versus 55.9 ± 1.1 in p53+/−). After 22 weeks of exercise, the EX mice displayed signficantly less percent body fat than sedentary controls, with no effect of genotype (44.4 ± 0.6 versus 47.8 ± 0.8 % respectively, p&lt;0.05). Immunoblot analysis revealed that in p53+/− mice, but not p53+/+ mice, exercise increased AMPK phosphorylation. This increased AMPK phosphorylation was associated with decreased phosphorylation of ribosomal protein S6, a marker of mTOR pathway activation (n=3/group). The observed increase in AMPK phosphorylation in p53+/− exercised mice relative to sedentary p53+/− was associated with decreased mRNA levels of sestrin 1 (n=4-6/group), indicating that the p53+/− mice may have higher levels of ROS in the MFP. In conclusion, exercise may increase AMPK activation in MFP of p53+/− mice relative to sedentary p53+/− mice through an ROS-mediated mechanism. Current analysis is focused on understanding how exercise affects AMPK activation in the mammary fat pad of MMTV-Wnt-1 transgenic mice heterozygous for p53, and how this impacts mammary tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5084.
Abstract 509: Novel role of MeCP2 in response to EGFR targeted therapy
Authors: Ramanand Susmita G. , Ahsan Aarif , Ao Xiaoping , Lubman David M. , Ray Dipankar , Lawrence Theodore S. , Nyati Mukesh K. 
Published: February 2011

Abstract
One of the targets towards the development of new agents to combat cancer is the inhibition of epidermal growth factor receptor (EGFR). A therapeutic antibody to EGFR, cetuximab, is seen to be effective in combination with cisplatin or radiation. However, only one out of four patients treated benefit from this therapy. It is therefore important to identify patients who can gain from this treatment. We hypothesize that through phosphoproteome analysis, we can identify alterations in novel signal transduction molecule(s) induced by cetuximab treatment in sensitive cell lines or TMA that will predict response to treatment. Phosphoproteomic changes upon cetuximab treatment in UMSCC-1 (cetuximab-responsive) and UMSCC-74B (cetuximab-non-responsive) cell lines using nonporous silica reverse-phase high performance liquid chromatography (NPS-RP-HPLC) were assessed. To confirm the results of phosphoproteomics data, three proteins that were seen to be affected in the sensitive cell line were investigated by immunoprecipitating total proteins followed by immunoblotting with phospho-specific antibodies. We found pharmacodynamic changes in 12 novel proteins upon cetuximab treatment in UMSCC-1 cell line. By Immunoblotting, we confirmed that these three proteins (methyl-CpG binding proteins) are indeed phosphorylated at serine, threonine and tyrosine sites. Cetuximab treatment in UMSCC-1, induced phosphorylation of NCoR1 and MeCP2 (which cause transcriptional repression) and decreased phosphorylation of MBD2 (which causes transcriptional activation), thus confirming the phosphoproteomic data. In contrast, the phosphoproteomics data in UMSCC-74B indicated either no effect or an opposing effect to that seen in the sensitive cells. These data suggest that we have a powerful strategy to identify novel phosphoproteins that are affected by EGFR inhibition and thus, novel biomarkers of response to cetuximab. These and additional biomarkers that we hope to discover will undergo rigorous in vitro and in vivo testing before employing them on TMA from xenografts.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 509.
Abstract 5099: Adiponectin inhibits oxidative stress in prostate cancer cells
Authors: Hou ZheFeng , Lu JianPing , Pinthus Jehonathan H. 
Published: February 2011

Abstract
INTRODUCTION AND OBJECTIVES: Emerging data suggest that obesity increases the risk of aggressive prostate cancer (PC) but the mechanisms underlying this relationship remain to be fully elucidated. Adiponectin, an adipocyte-specific hormone, circulates at relatively high levels in healthy human but its levels are reduced in obesity. Case control studies have documented an association between lower adiponectin blood levels and PC implying that obese individuals with low adiponectin levels are more susceptible in developing PC. In this study we examined the effect of adiponectin on the generation and reduction of oxidative stress (OS) in PC cells, a process that intimately relates to the initiation and development of PC.
METHOD: As models we used two human PC cell lines (22rv1 and DU145) expressing the adiponectin receptors AdipoR1, AdipoR2 and T-cadherin. Cells were treated with increasing doses of human recombinant adiponectin (0-40μg/ml) and were subjected to the following tests: Quantification of cellular OS (NBT reduction assay), expression of catalase and MnSOD (Western blot analysis), comparison of transcript levels of NADPH oxidases (NOX) enzymes- a major source of reactive oxygen species in PC cells (RT-PCR) and determination of the global cellular anti-oxidative capacity and catalase activity (colorimetric assays).
RESULT: Adiponectin significantly inhibited OS in both cell types in a dose dependent manner by inducing the expression of the two key anti-oxidative enzymes; catalase and MnSOD, leading to an increase in the anti-oxidative capacity of the cells. Treatment with adiponectin reduced Nox 2,4 mRNA expression in Du145 cells but increased it in 22RV1 cells.
CONCLUSIONS: These results suggest a protective role for adiponectin against the initiation and development of PC, through OS inhibition.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5099.