bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1559: Targeting the PH domain of Tiam-1 to inhibit breast cancer metastasis
Authors: Moses Sylvestor A. , Song Zuohe , Du-Cuny Lei , Powis Garth , Mash Eugene , Zhang Shuxing , Meuillet Emmanuelle J. 
Published: February 2011

Abstract
TIAM-1 (T-lymphoma invasion and metastasis-inducing protein-1) is a highly conserved guanine nucleotide exchange factor and contains an N-terminal pleckstrin homology domain (PHn) and a Dbl homology (DH)/C-terminal PH domain (PHc). While no crystal structure exists for the PHn of TIAM-1, the crystal structure of DH-PHc of TIAM-1 in complex with Rac-1 has been reported. TIAM-1 has been found to be over-expressed in breast, colon and prostate cancers. An increase in TIAM-1 expression has been shown to be associated with increased metastatic potential of breast cancer cell lines. TIAM-1 is thus an ideal PH domain drug target directly related to cancer progression, metastasis and patient survival. In this study, we have identified novel small molecule inhibitors targeting the phosphoinositide (PtdIns) lipid binding PHc domain of TIAM-1 in order to selectively inhibit cell migration and survival. Utilizing an In Silico screen of our internal and Maybridge library and the crystal structure of TIAM-1, we have found 29 compounds that bind to PHc TIAM-1. In vitro assays have revealed that compound PH-210 and #10 significantly reduced the amount of active Rac1 and binds to PHc-TIAM-1 with high affinity (KD in the micromolar range) using surface plasmon resonance (SPR) spectrometry. Both compounds displace PtdIns-3,4,5-P3 in a SPR competitive binding assay. Ongoing in vivo studies using MDA-231 breast cancer cell lines will determine the anti-tumor activity of these compounds. Overall, these novel compounds could exhibit the ability to significantly reduce breast cancer metastasis by binding to PHc-TIAM-1 and could have the potential to be used with other chemotherapeutic compounds as part of an effective breast cancer treatment regimen.
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 1559.
Abstract 1562: PYK2 and FAK in breast cancer
Authors: Zhai Ling , Li Rongbao , Qu Zhican 
Published: February 2011

Abstract
Proliferation and invasion of malignant tumor cells are mediated by multiple events, including activation of focal adhesion signalings and cytoskeleton remodeling. Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are cytoplasmic tyrosine kinases identified as key mediators in regulation of cytoskeleton proteins in focal adhesion. Pyk2 were found to be overexpressed in Glioblastoma and played a central role in brain tumor invasion. Studies also showed that FAK increased expression and activation in various human cancers. Recently, studies with patients’ tumor samples have demonstrated that Pyk2 and FAK are co-overexpressed in over 70% human breast cancers from the very early disease stage of in situ carcinoma to the advanced metastatic stage. Pyk2 was also involved in the cytoskeleton changes initiated by heregulin through the ErbB-2 receptor in breast cancer cell lines. To further investigate role of Pyk2 and FAK in breast cancer progression and metastasis, we studied protein expression and activation of Pyk2 and FAK, as well as their substrates and interacting proteins in human breast cancer and normal breast epithelial cell lines. Our results showed that activation of both Pyk2 and FAK are marked increased in breast cancer cell lines in comparison with normal breast epithelial cells. In addition, serum stimulation was able to further activate Pyk2 and FAK and to increase tyrosine phosphorylation of their substrates and interacting proteins, including paxillin, Src, and p130CAS. The activated Pyk2 and FAK formed protein complex with paxillin, Src, and p130CAS. Our results and other published studies support the cooperative function of Pyk2 and FAK in breast cancer progression and suggest that dual inhibition of Pyk2 and FAK is a potential therapeutic approach for invasive breast cancer. Lead compounds of Pyk2 and FAK inhibitors have been identified by Southern Research drug discovery team and will be further evaluated in vitro and in vivo as potential breast cancer treatment.
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 1562.
Abstract 1566: Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in diffuse-type gastric carcinoma
Authors: Yashiro Masakazu , Shinto Osamu , Kato Yukihiro , Kashiwagi Shinichiro , Fuyuhiro Yuhiko , Matsuoka Junko , Doi Yosuke , Noda Satoru , Morimoto Junya , Yamazoe Sadaaki , Matsuoka Tasuku , Tanaka Hiroaki , Ohira Masaichi , Sawada Tetsuji , Hirakawa Kosei 
Published: February 2011

Abstract
Background: Vascular endothelial growth factor receptor-3 (VEGFR-3) signaling mediates lymphangiogenesis and lymphatic invasion, however the effect of VEGFR-3 inhibition on the lymph node (LN) metastasis remains unclear. The aim of this study is to clarify the benefit of a VEGFR-3 inhibitor Ki23057 for LN metastasis.
Methods: Ki23057 was administered orally to gastric cancer models created by orthotopic inoculation of diffuse-type gastric cancer cells, OCUM-2MLN. Effects of Ki23057 on lymphatic vessel invasion, lymphatic vessel density, and VEGFR-3 phosphorylation were examined by immunostaining or immunoblotting.
Results: Ki23057 inhibited the autophosphorylation of VEGFR-3 with IC50 values of 4.3 nM in the cell-free kinase assay. Murine gastric cancer models created by the orthotopic inoculation of OCUM-2MLN cells showed the diffusely infiltrating growth and frequently developed LN metastasis. The oral administration of Ki23057 significantly (p&lt;0.01) reduced the size of orthotopic tumors and the number of the metastatic LN in gastric cancer models. The degree of lymphatic invasion and lymphangiogenesis was significantly (p&lt;0.05) lower in the gastric tumors treated by Ki23057. Ki23057 inhibited the phosphorylation of VEGFR-3 of lymphatic endothelial cells in gastric tumors.
Conclusion: The inhibition of lymphangiogenesis targeting VEGFR-3 phosphorylation is a therapeutic strategy for inhibiting LN metastasis of diffuse-type gastric cancer.
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 1566.
Abstract 1567: The multi-targeted kinase inhibitor Sunitinib blocks VEGF-C signaling pathway and lymphangiogenesis
Authors: Yasuo Kodera , Katanasaka Yasufumi , Kitamura Yuuka , Tamura Tomohide , Koizumi Fumiaki 
Published: February 2011

Abstract
Metastasis is the main cause of therapeutic failure and death in cancer patient. Tumor cells disseminate to distant organs through lymphatic and blood vessels. The degree of metastasis in regional lymph nodes is a prognostic factor and determines treatment course of patients.
Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) family regulate angiogenesis and lymphangiogenesis. Several clinical studies have shown that the expression of VEGF-C is associated with lymphangiogenesis and lymph node metastasis in many different types of cancer.
Sunitinib is a tyrosine kinase inhibitor that inhibits VEGFR, PDGFR, KIT, FLT3, RET, and CSF1R. The main mechanism for tumor growth inhibition is thought to be anti-angiogenic effect by inhibiting VEGFR-2 kinase activity. However, the effect of sunitinib on VEGF-C/VEGFR-3 pathway and lymphangiogenesis remain unclear.
Therefore, we evaluated the effect of sunitinib on lymphangiogenesis with using lymphatic endothelial cell (LEC) and imaging breast cancer model. Sunitinib inhibited VEGF-C-induced phosphorylation of VEGFR-3, Akt and ERK1/2 at submicromolar level in LEC. Additionally, the growth and tube formation were also blocked by sunitinib. Furthermore, sunitinib treatment significantly suppressed tumor lymphangiogenesis and axillary lymph node metastasis as evaluated by photon counting method.
These results suggest that Sunitinib may be beneficial for breast cancer patients by inhibiting lymph node metastasis.
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 1567.
Abstract 1574: The impact of human wild type EGFR on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies
Authors: Chen Liang , Ercan Dalia , Cho Jeonghee , Janne Pasi A. , Meyerson Matthew L. , Wong Kwok-Kin 
Published: February 2011

Abstract
Lung cancer is the leading cause of the cancer related death in the world. Non-small cell lung cancer is the major lung cancer type, of which more than 1.4 million new cases were diagnosed each year. Overexpression of wild type EGFR is common in NSCLC. However, it is not clear whether or not overexpression of wt EGFR is tumorigenic. We recently showed that overexpression of wt-hEGFR is capable of transforming cell lines. More importantly, inducible double transgenic mice overexpressing wt-hEGFR in lung epithelial compartment developed poorly differentiated lung adenocarcinoma and that the maintenance of the tumor is dependent on continuous functioning of wt-hEGFR. The tumor driven by overexpression of wt-hEGFR responds to cetuximab and erlotinib treatment.
These data suggest that a subpopulation of the lung cancer may be caused by overexpression of wt-hEGFR and that these lung cancers can be treated with anti-EGFR antibodies and EGFR tyrosine kinase inhibitors.
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 1574.
Abstract 1575: Bortezomib selectively induces apoptosis in hematological malignant cells through down-regulation of phospho-Akt independent of its proteasome inhibitory activity
Authors: Liu Chun-Yu , Shiau Chung-Wai , Cheng Ann-Lii , Kuo Hsin-Yu , Tzeng Cheng-Hwai , Chen Kuen-Feng 
Published: February 2011

Abstract
Background: Bortezomib, a proteasome inhibitor (PI), has excellent clinical activity in patients with multiple myeloma and mantle cell lymphoma. Our previous study has shown that down-regulation of phospho-Akt (P-Akt) plays a key role in determining the sensitivity of hepatocellular carcinoma cells to bortezomib-induced apoptosis. (Cancer Res, 2008). Here, we further examined whether P-Akt is associated with the drug sensitivity of hematological malignant cells toward bortezomib. Methods: Several hematological malignant cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). Results: Bortezomib induced apoptosis in association with down-regulation of P-Akt in a dose- and time-dependent manner in sensitive cells (HL-60) but not in resistant K562 cells. Down-regulation of Akt1 by small interference RNA overcame the apoptotic resistance to bortezomib in K562 cells whereas a constitutively activated Akt1 protected HL-60 cells from bortezomib-induced apoptosis. Importantly, bortezomib showed the similar inhibition of the proteasome activity in both sensitive and resistant cells, suggesting that bortezomib-induced apoptotic effect may not depend on its proteasome inhibitory effect. Conclusions: Down-regulation of P-Akt plays an important role in bortezomib-induced apoptosis in hematological malignancies. Targeting on Akt signaling, either directly or through upstream regulation, provides an attractive approach to overcome bortezomib resistance in certain hematological malignancies. Supported by VGHTPE 99DHA0100332
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 1575.
Abstract 1579: Depletion of GAPDH promotes p53 signaling, cell senescence and altered response to chemotherapeutic agents in human carcinoma cells
Authors: Phadke Manali S. , Krynetskaia Natalia , Krynetskiy Evgeny 
Published: February 2011

Abstract
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a pivotal enzyme of the glycolytic pathway; it also plays a role of a signaling/regulator molecule in several cellular networks. In this study, we used human lung carcinoma A549 and renal carcinoma UO-31 cell lines to elucidate the role of GAPDH in cell proliferation and cellular response to genotoxic drugs. Using RNA interference technology, we decreased GAPDH protein level 4-5-fold in A549 cells, and 2-3-fold in UO-31 cells. Depletion of GAPDH in cultured cells blocked cell cycle progression in G1 phase, and induced activation of p53 and accumulation of p21. Simultaneously, GAPDH-depleted cells manifested biomarkers of senescence as revealed by morphological changes and induction of SA-β-galactosidase activity. Inhibition of GAPDH synthesis in human carcinoma cells resulted in 3-4-fold ATP depletion, and induced cell growth arrest without AMPK phosphorylation. In contrast, inhibition of glycolysis by 2-deoxyglucose treatment resulted in decreased ATP level and AMPK phosphorylation but did not induce cell senescence. These results suggest that GAPDH depletion in A549 cell line activates p53 independently of AMPK activation, and mediates the induction of signaling pathways leading to senescence. Importantly, GAPDH knockdown in p53-proficient A549 and UO-31 cells resulted in 3-50-fold decreased cytotoxicity of antimetabolite drugs including deoxy-thioguanosine, cladribine, fluoro-ribouridine, fluoruracil, 2-chloroadenosine, mercaptopurine, azacytidine and cytarabine. The results of this study indicate that cytotoxic activity of antimetabolite nucleoside analogs is modulated by the status of GAPDH in the cancer cells. Cell senescence induced by depletion of GAPDH is a plausible mechanism of cell resistance to antimetabolites, a hypothesis being under investigation in our lab. In addition, our data indicate that GAPDH-depleting agents could be promising cytostatic drugs.
This work was supported by NCI grant R01 CA104729
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 1579.
Abstract 1580: Differential induction of reactive oxygen species by histone deacetylase inhibitors for mediating selective apoptosis of oncogenic H-Ras-expressing cells
Authors: Choudhary Shambhunath , Wang Hwa-Chain R. 
Published: February 2011

Abstract
This study is to understand the mechanisms involved in the reactive oxygen species (ROS)-mediated pro-apoptotic ability of H-Ras to enhance apoptosis induced by histone deacetylase inhibitors (HDACIs). Oncogenic induction of the ras genes is widely involved in human cancers. Expression of oncogenic H-Ras increases susceptibility of human and mouse cells to HDACIs, such as FK228 and trichostatin A, for inducing caspase activation and selective apoptosis. To understand the mechanisms for HDACI-induced differential activation of caspases and apoptosis in oncogenic H-Ras-expressing cells, we investigated the role and regulation of ROS in HDACI-induced cell death. We detected that expression of oncogenic H-Ras resulted in potentiating intracellular ROS machinery, increasing the susceptibility to HDACIs for enhancing the production of ROS, and depleting glutathione, leading to differential activation of caspases and cell death. Furthering our understanding of how oncogenic H-Ras augmented the generation of ROS, we detected that expression of oncogenic H-Ras was able to increase the level of Nox1, a homologue of the catalytic subunit of the superoxide-generating NADPH oxidase. Suppression of Nox1 by the specific inhibitor diphenylene iodonium or specific siRNAs significantly reduced ROS production induced by oncogenic H-Ras and HDACIs as well as HDACI-induced cell death of oncogenic H-Ras-expressing cells. Our results led us to a suggestion that increased ROS played a contributing role in the proapoptotic ability of oncogenic H-Ras to enhance HDACI-induced activation of caspases for inducing selective apoptosis in a dose-dependent manner; Nox1 played an important role in the ability of oncogenic H-Ras to potentiate ROS-producing machinery for enhancing cell susceptibility to HDACIs and, in turn, increasing ROS contents leading to caspase activation and selective apoptosis. Differential increases of intracellular ROS by oncogenic H-Ras to potentiate cell death should be seriously considered as a potential target in developing therapeutic strategies to control oncogenic H-Ras-involved human cancers by HDACIs.
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 1580.
Abstract 1585: Loss of CDK5 sensitizes ovarian cancer cells to paclitaxel by enhancing intracellular retention
Authors: Ahmed Ahmed A. , Le Xiao-Feng , Lu Zhen , Mao Maggie , Aiken Abigail , Bast Robert C. 
Published: February 2011

Abstract
In order to improve the efficacy of paclitaxel in treatment of ovarian cancer, we have performed a kinome siRNA library screen to identify kinases that regulate paclitaxel sensitivity. CDK5 was one of kinase targets that could modulate paclitaxel sensitivity in SKOv3 cells. Unlike typical cyclin dependent kinases, CDK5 does not have a clearly defined role in the regulation of the cell cycle. CDK5 is required for the regulation of neuronal synaptic vesicular transport in the brain through phosphorylation of Munc 18, a key regulator of vesicular exocytosis. In this report, we aimed to explore the mechanisms by which CDK5 potentiate paclitaxel activity. We found that eighteen ovarian cancer cell lines expressed variable CDK5 levels measured by quantitative real time PCR and Western blotting. Basal levels of CDK5 in ovarian cancer cell lines appeared not to correlate with paclitaxel sensitivity. We used immunoprecipitation of CDK5 and in vitro kinase assays using 32P-ATP and observed that paclitaxel treatment of SKOv3 cells resulted in a profound (&gt;20 fold) increase in CDK5 activity. Selective depletion of CDK5 using 4 individual siRNAs in SKOv3, TOV112 and DOV13 ovarian cancer cells lines resulted in a significant increase in paclitaxel-induced cytotoxicity as measured by cell viability assays. In addition, loss of CDK5 resulted in a significant increase in paclitaxel-mediated induction of caspase 3/7 activation in the ovarian cancer cell lines SKOv3, ES2, OVAR429 and DOV13. Remarkably, the magnitude of sensitization was directly proportional (p&lt;0.001) to the dose of paclitaxel used. Knockdown of CDK5 did not enhance microtubule stabilization or increase paclitaxel-induced mitotic arrest. Instead, CDK5 depletion in SKOv3 cells resulted in a significant (p&lt;0.001) increase in retention of fluorescent-tagged paclitaxel. This effect was similar to but independent from the effect of inhibition of trans-membrane pumps using verapamil, suggesting that the two mechanisms act in parallel. Indeed, knockdown of CDK5 in combination with verapamil resulted in greater intracellular retention of paclitaxel in SKOv3 cells. Consequently, we conclude that depletion of CDK5 results in decreased paclitaxel exocytosis leading to increased cytotoxicity to ovarian cancer cells.
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 1585.
Abstract 159: LINE-1 hypomethylation and patient prognosis in 1118 colorectal cancers
Authors: Ogino Shuji , Nosho Katsuhiko , Schernhammer Eva , Giovannucci Edward , Fuchs Charles 
Published: February 2011

Abstract
Background: Global DNA hypomethylation plays an important role in activation of oncogenes in a genome-wide scale, chromosomal instability and colorectal carcinogenesis. DNA methylation in LINE-1 (L1) repetitive element has been correlated with global DNA methylation level. We examined LINE-1 methylation in colorectal cancer and patient survival.
Methods: Utilizing 1118 colorectal cancers in two prospective cohorts, we quantified methylation in a LINE-1 by Pyrosequencing. Kaplan-Meier method and Cox proportional hazard models were used to assess differences in colon cancer-specific and overall mortalities in univariate analysis and multivariate analysis that adjusted for patient characteristics and tumoral molecular features, including BRAF mutation, the CpG island methylator phenotype and microsatellite instability.
Results: LINE-1 hypomethylation in 875 colon cancers was independently and linearly associated with high colon-cancer specific mortality (Ptrend&lt;0.0001) and overall mortality (Ptrend=0.0004). Compared to patients with ≥75% LINE-1 methylated tumors, the adjusted hazard ratio (HR) for colon cancer-specific mortality were 1.36 [95% confidence interval (CI), 0.76-2.41] for 60-75% LINE-1 methylated tumors, 1.98 (95% CI, 1.10-3.55) for 45-60% LINE-1 methylated tumors, and 3.83 (95% CI, 1.87-7.84) for &lt;45% LINE-1 methylated tumors. Similar findings were noted for overall mortality. Kaplan-Meier analysis demonstrated shorter survival among patients with LINE-1 hypomethylated tumors (log-rank p&lt;0.0001). The prognostic influence of LINE-1 hypomethylation in colon cancer was consistent across the two independent cohort studies as well as across strata of clinical or molecular characteristics. In contrast, LINE-1 hypomethylation was not significantly associated with survival of 243 rectal cancer patients (adjust HR 1.02; 95% CI, 0.48-2.19; for a 30% decrease of LINE-1 methylation; Ptrend=0.96).
Conclusions: Tumoral LINE-1 hypomethylation is associated with shorter survival among colon cancer patients.
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 159.