bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2232: Overexpression of the mu opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth and metastasis
Authors: Lennnon Frances E. , Mirzapoiazova Tamara , Mambetsariev Bolot , Salgia Ravi , Moss Jonathon , Singleton Patrick A. 
Published: August 2012

Abstract
Background: Recent epidemiologic studies suggesting that there were differences in cancer recurrence contingent on anesthetic regimens have raised the possibility that mu opioid agonists can influence cancer progression. Based on our previous studies indicating the mu opioid receptor (MOR) is upregulated in several types of non-small cell lung cancer (NSCLC), this study examined the functional significance of MOR overexpression to elucidate a possible mechanism for the epidemiologic findings. Methods: Stable vector control (VC) and MOR1 overexpressing human NSCLC bronchioloalveolar carcinoma (BAC) cells were evaluated using immunoblot analysis, proliferation and transendothelial extravasation assays with or without Akt inhibitor, mTOR inhibitor (temsirolimus) or the peripheral MOR antagonist, methylnaltrexone (MNTX). In human NSCLC xenograft models, primary tumor growth rates and lung metastasis were analyzed using consecutive tumor volume measurements and nestin immunoreactivity in nude mouse lungs. Results: We provide evidence that MOR is an important regulator of lung cancer progression, a disease with high mortality and few treatment options. MOR overexpression increased Akt and mTOR activation, proliferation and extravasation in human BAC cells. In vivo, overexpression of MOR in BAC increased primary tumor growth rates in nude mice by ∼2.5 fold and lung metastasis by ∼20 fold compared to VC BAC cells. Conclusions: Our overexpression data suggests a possible direct effect of MOR on Akt and mTOR activation and lung cancer progression. Such an effect provides a plausible explanation for the epidemiologic findings. Our observations further suggest that exploration of MOR in NSCLC merits further study both as a diagnostic and therapeutic option.
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 2232. doi:1538-7445.AM2012-2232
Abstract 2234: Activation of PI3K pathway by P-Rex2 is inhibited by GNMT
Authors: Li Chung-Hsien , Yen Chia-Hung , Chen Mei-Yu , Chen Yi-Ming 
Published: August 2012

Abstract
Glycine N-methyltransferase (GNMT) is a tumor suppressor for hepatocellular carcinoma (HCC). Previously, we reported that GNMT regulates mTOR signaling pathway through interacting with an mTOR binding protein-DEPTOR. Sequence blasting and phylogenetic analysis demonstrated that the first DEP domain of DEPTOR clustered with P-Rex2, a regulator of the small guanosine triphosphatase Rac. Since P-Rex2 has been showed to be able to antagonize PTEN in PI3K pathway, the aims of this study was to analyze the interaction between GNMT and P-Rex2 and their association in PI3K-Akt signaling pathway. Gel filtration assay demonstrated that GNMT and P-Rex2 were eluted in the same fractions. Reciprocal co-immunoprecipitation experiments demonstrated that GNMT interacts with different domains of P-Rex2 including DH, PH, PDZ and InsPx4-Phosphatase. Overexpression of P-Rex2 enhanced Akt activation in HCC cell line as well as in breast cancer cell lines and such effect was blocked by over-expression of GNMT. Pulse-chase experiments showed that overexpression of GNMT caused significant reduction of the half-life of P-Rex2 from 15 hr to 9.5 hr. Finally, overexpression of GNMT in HuH-7 cells resulted in a proteasome-dependent degradation of P-Rex2. Therefore, GNMT affects PI3K-Akt pathway via direct binding with P-Rex2 and enhance its degradation.
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 2234. doi:1538-7445.AM2012-2234
Abstract 2243: Targeting the MUC1-C oncoprotein synergistically enhances cytotoxicity of breast carcinoma cells in combination with PI3K inhibitors
Authors: Raina Deepak , Kharbanda Surender , Kufe Donald 
Published: August 2012

Abstract
The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed by most human breast carcinomas and contributes to the malignant phenotype. However, there are no effective agents that directly inhibit the oncogenic MUC1-C subunit and induce death of breast cancer cells. We have synthesized MUC1-C peptide inhibitors that bind to the MUC1-C cytoplasmic domain and block the formation of MUC1-C dimers in breast cancer cells. We have shown that inhibition of MUC1-C arrests growth and induces necrotic death of the breast carcinoma cells. Here we demonstrate that combining the MUC1-C inhibitor GO-203-2C with agents that target PI3K (LY294002, GDC0941) induces highly synergistic cytotoxicity of breast carcinoma cells. Notably, GO-203-2C significantly enhanced the effectiveness of these PI3K inhibitors by contributing to the downregulation of p-AKT and p-S6K. Taken together, these findings provide support for combining PI3K inhibitors and GO-203-2C, an agent now undergoing Phase I evaluation, to improve treatment of patients with breast cancer.
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 2243. doi:1538-7445.AM2012-2243
Abstract 2256: PDEF regulation and role as a survival factor in ER positive breast cancer cells
Authors: Buchwalter Gilles , Brown Myles 
Published: August 2012

Abstract
PDEF (Prostate Derived Ets Factor) is a member of the ‘Ets’ family. These transcription factors regulate a number of biological processes, including cell proliferation, differentiation, invasion and are thought to play an important role in oncogenesis. PDEF is expressed exclusively in tissues with a high epithelial content, especially hormone-regulated epithelium, such as prostate, mammary gland, endometrium and ovary. Furthermore, several studies showed PDEF to be one of the most highly over expressed mRNA in human and mouse mammary tumors. PDEF is interestingly significantly co-expressed with ER in ER positive breast carcinomas, together with known ER cofactors such as FOXA1, XBP1 and GATA3. PDEF was previously characterized as an Androgen Receptor cooperating factor in prostate, however its potential function as an ER cofactor is not explored yet. We investigated the mechanism of this ER/PDEF co expression and the role of PDEF in breast cancer cells. Using siRNA downregulations, mRNA quantification, and Chromatin IP, we discovered that the mechanism of ER/PDEF co expression implies a critical role for GATA3 as a negative regulator of PDEF expression. Moreover PDEF and GATA3 expressions are inversely correlated in ER positive Breast Cancer and cell lines. Kaplan-Meier survival analyses showed that these two factors could be useful prognosis markers for patients. We performed growth curves, cell cycle (FACs) and apoptosis (Annexin V) analyses of MCF7 cells transfected with a PDEF targeting siRNAs. The growth curves revealed an impaired proliferation rate of PDEF downregulated cells. Quantification of apoptosis in various conditions (basal, stress induced) demonstrated that PDEF is an essential survival factor for breast cancer cells. The loss of PDEF expression indeed triggers an increased proportion of apoptotic cells, especially in stress conditions such as hormone depletion or tamoxifen / fulvestrant treatments. The findings presented in this poster are evidences that designate PDEF as a potential new cofactor of ER and as an interesting therapeutic target, since its down regulation makes breast cancer cells more prone to undergo apoptosis in stress conditions.
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 2256. doi:1538-7445.AM2012-2256
Abstract 2262: Contribution of autophagy in anticancer immune response induced by chemotherapy
Authors: Sukkurwala Abdul Qader , Michaud Mickaël , Martins Isabelle , Kroemer Guido 
Published: August 2012

Abstract
Antineoplastic chemotherapies are particularly efficient when they elicit immunogenic cell death, thus provoking an anticancer immune response. We demonstrate that autophagy, which is often disabled in cancer, is dispensable for chemotherapy-induced cell death but required for its immunogenicity. In response to chemotherapy, autophagy-competent, but not autophagy-deficient, cancers attracted dendritic cells and T lymphocytes into the tumor bed. Suppression of autophagy inhibited the release of adenosine triphosphate (ATP) from dying tumor cells. Conversely, inhibition of extracellular ATP-degrading enzymes increased pericellular ATP in autophagy-deficient tumors, re-established the recruitment of immune cells, and restored chemotherapeutic responses, but only in immunocompetent hosts. Thus, autophagy is essential for the release of immunogenic ATP from dying cells, and increased extracellular ATP concentrations improve the efficacy of antineoplastic chemotherapies when autophagy is disabled.
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 2262. doi:1538-7445.AM2012-2262
Abstract 2264: Autophagy inhibition sensitizes the growth inhibitory effects of propolin C but not propolin G on human lung adenocarcinoma A549 cells
Authors: Hsu Hui-Chen , Wang Hsiao-Feng , Chen Yu-Fen , Chen Yue-Wen , Chen Wei-Jung , Tsai Meng-Feng 
Published: August 2012

Abstract
Propolins, prenylflavanones are isolated and characterized from Taiwanese propolis, have been shown inhibits certain cancer cell lines growth and induced apoptosis. In our previous study, Taiwanese propolis, propolin C and porpolin G, could promote LC3B increased within 6 hours treatment, moreover, and AVOs (acidic vesicular organelles) significantly increased by AO (Acridine orange) staining. The autophagy induced by propolin C or propolin G is accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Flow cytometry assay showed that sub-G1 phase increased significantly in propolin G treatment but not in propolin C treatment. Autophagy pharmacological inhibitors, 3-methyladenine and Chloroquine were used to test whether autophagy blockade could lead to enhance cell death. The results showed that only autophagy inhibitor chloroquine effectively enhanced apoptosis induced by propolin C but not propolin G in A549 cells. The expression of pERK and pAkt was suppressed dramatically by autophagy inhibitor in combination with propolin C. Ectopic expression of mutant Akt (constitutive active) in A549 cells abolished chloroquine sensitization effect of propolin C. Together, autophagy serves a protective role in propolin C-mediated cytotoxicity, and autophagy modulators may be used as adjunctive therapeutic agents for propolin.
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 2264. doi:1538-7445.AM2012-2264
Abstract 227: Overexpression of EphB1 leads to Stat3 phosphorylation
Authors: Gechtman Zev 
Published: August 2012

Abstract
The Receptor Tyrosine Kinase (RTK) family comprises some important disease drivers. Over-expressed or mutated RTKs in disease may lead to aberrant phosphorylation of intracellular signaling molecules. Therefore it is desirable to monitor simultaneously the activation levels of RTKs and signaling nodes. Here we used a multiplexed antibody array to monitor the phosphorylation of 28 RTKs and 11 intracellular signaling molecules simultaneously. We have observed a strong signal on a spot corresponding to phospho-STAT3 Tyr705 with lysates derived from CHO cells transiently over-expressing EphB1. The strong Phospho-STAT3 signal was not seen in non-transfected cells or in lysates made form cells transfected with several other Eph family members. Western blotting with phospho-specific antibodies showed an increase in STAT3 phosphorylation on Tyr705 in CHO cells upon EphB1 ectopic expression. The amounts of Tyr705 STAT3 phosphorylation positively correlated with the levels of EphB1 protein. Co-precipitation experiments showed that EphB1 and STAT3 interact both in CHO cells and MCF-7 breast cancer cells. Phosphorylated JAK2 was not found in these immuno-precipitates suggesting an involvement of another tyrosine kinase in STAT3 phosphorylation in cells over-expressing EphB1. Consistently with these observations, a potent JAK1 and JAK2 inhibitor INCB018424 inhibited the basal but not the EphB1-induced STAT3 Tyr705 phosphorylation in transfected CHO cells. These results suggest that EphB1 over-expression may bypass the requirement in Jak kinase and lead to STAT3 activation either directly or through another receptor-tethered kinase.
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 227. doi:1538-7445.AM2012-227
Abstract 2274: Docosahexaenoic acid-induced cell death may be related to inhibition of mTOR through AMPK activation and PI3K/Akt inhibition in human non-small cell lung cancer cells
Authors: Lim Kyu , Kim Nayeong , Jing Kaipeng , Jeong Soyeon , Shin Soyeon , Oh Hyerim , Jo Eun-Ah , Heo Jun-Young , Park Ji-Hoon , Seo Kang-Sik , Song Kyoung-Sub , Han Jeongsu , Park Jong-Il , Park Seung-Kiel , Kweon Gi-Ryang , Yoon Wan-Hee , Hwang Byung-Doo 
Published: August 2012

Abstract
Over 80% of the lung cancer patients have non-small cell lung cancer (NSCLC). Although the anticancer mechanisms of omega-3 polyunsaturated fatty acids (≥3-PUFAs) have been reported in several cancers, it is still unclear in lung cancer. In this study, we have identified a novel anticancer effect of docosahexaenoic acid (DHA), a α3-PUFAs, on NSCLC. DHA induced cytotoxicity and morphology change in A549 and H1299 NSCLC cells and was confirmed that apoptosis and autophagy are responsible for the cytotoxicity induced by DHA. DHA increased AMPK activity and inhibited PI3K/Akt signaling as well as mTOR signaling molecules. Knockdown AMPK using small interfering RNAs specific for AMPK and overexpression Akt significantly enhanced the mTOR activity and attenuated the cell death caused by DHA treatment, indicating that DHA induces NSCLC cell death via the AMPK- and Akt-regulated mTOR inactivation. We also confirmed this effect of α3-PUFAs in vivo using Fat-1 transgenic mice that are capable of producing α3-PUFAs. When mouse lung cancer LLC cells were subcutaneously implanted into Fat-1 mice, the growth of tumor was markedly inhibited with decrease the level of p-Akt as well as increases in TUNEL-positive staining cells and autophagic levels, compared to wild-type mice. Taken together, these data suggest that the apoptosis and autophagy induced by DHA may be related to mTOR inhibition through AMPK activation and PI3K/Akt inhibition in NSCLC. Therefore, utilization of DHA may represent a potential effective therapy for the chemoprevention and treatment of human non-small cell lung cancer. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (2011-0013263 and 2011-0006232)]
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 2274. doi:1538-7445.AM2012-2274
Abstract 2275: A novel heat shock protein 90 inhibitor, NVP-AUY922, enhances the antitumor effect of imatinib via autophagy on imatinib-resistant CML cells
Authors: Osato Yoichi , Yokoyama Tomohisa , Hayabe Hiroko , Miyasato Akime , Akashi Takao , Komatsu Seiichiro , Tauchi Tetsuzo , Ohyashiki Kazuma 
Published: August 2012

Abstract
The BCR-ABL tyrosine kinase inhibitor (TKI), imatinib mesylate, has revolutionized the treatment of CML, however, the development of TKI-resistance caused in approximately 10-25% of cases by mutation in the BCR-ABL kinase domain. Therefore, novel therapeutic strategies are needed to address the emerging problem of imatinib-resistant CML. Recently, the heat shock proteins of 90 kDa (Hsp90) have emerged as targets of interest in cancer therapy. NVP-AUY922 (Novartis) is a novel 4, 5-diaryloxazole ATP-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and delete the levels of HSP90 client protein including BCR-ABL. We have recently reported that combined treatment of NVP-AUY922 and BCR-ABL TKI exhibits a desirable therapeutic index that can reduce the in vivo growth of mutant form of BCR-ABL-expressing cells (Oncogene 30, 2789-97, 2011). However, the mechanism of programmed cell death (PCD) is not yet completely understood. In the present study, we examined the mechanism of PCD induction by the combined treatment of NVP-AUY922 and imatinib on wild-type (WT) and mutant forms of BCR-ABL Baf-3 cells (E255K and T315I). Imatinib-mediated inhibitory effect was observed on WT cells, however, E255K and T315I cells were less sensitive to imatinib than WT cells. BCR-ABL mutant T315I cells were the most resistant to imatinib. On the other hands, NVP-AUY922 was synergistically sensitized tumor cells to imatinib on both WT and imatinib-resistant Baf-3 cells. Activity of caspase-3/7 was increased by combined treatment with imatinib and/or NVP-AUY922 on WT cells, indicating induction of apoptosis. In contrast, apoptosis induced by combined treatment with imatinib and/or NVP-AUY922 was significantly suppressed, although the inhibition of cell growth was still detectable on E255K and T315I cells. May-Giemsa staining revealed that many vacuoles were detected in the cytoplasm by combined treatment with imatinib and NVP-AUY922 on E255K and T315I cells, indicating the morphologic features of autophagy. We are currently conducting autophagy-detection assay and determining autophagic signaling pathways. Our findings indicate that NVP-AUY922 enhances the antitumor effect of imatinib, through activation of autophagy on imatinib-resistant CML cells. These data strongly suggest that combined treatment of imatinib and NVP-AUY922 is a novel approach for the treatment of patients with imatinib-resistant CML.
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 2275. doi:1538-7445.AM2012-2275
Abstract 228: PAK1 kinase promotes cell motility through CRK serine phosphorylation in non-small cell lung cancer cells
Authors: Mortazavi Fariborz (Fred) , Rettig Matthew 
Published: August 2012

Abstract
The role of c-Crk (CRK) in promoting metastasis is well described but the role of CRK phosphorylation and the corresponding signaling events are not well explained. We have noticed that CRK serine 41 phosphorylation is inversely correlated with p120-catenin and E-cadherin expressions in non-small cell lung cancer (NSCLC) cells. Therefore, we investigated the role of CRK serine 41 phosphorylation in the down-regulation of p120-catenin and cell motility in NSCLC cells. We prepared A549 cell lines stably expressing phosphomimetic and phosphodeficient CRK serine 41 constructs. A549 cells expressing phosphomimetic CRK seine 41 demonstrated a more aggressive behavior in would healing assay and on the contrary, expression of phosphodeficient CRK serine 41 in A549 cells reduced cell motility. A549 cells expressing phosphomimetic CRK serine 41 had lower p120-catenin mRNA and promoter activity and vice versa. In addition, we provide evidence that PAK1 mediates CRK serine 41 phosphorylation. RNAi mediated silencing of PAK1 increased p120-catenin level and also decreased cell motility in A549 and H157 cells. These effects were abrogated in A549 cells expressing phosphomimetic CRK serine 41. In summary, our data provide evidence for the role of PAK1 in promotion of cell motility and down regulation of p120-catenin through CRK serine 41 phosphorylation in NSCLC cells.
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 228. doi:1538-7445.AM2012-228
Abstract 2282: Targeting oncogenic NDRG4: A promising strategy for meningioma treatment
Authors: Kotipatruni Rama Prasadarao , Ren Xuan , Vanderwaal Robert , Thotala Dinesh Kumar , Jaboin Jerry 
Published: August 2012

Abstract
Meningiomas are the second most common brain tumors, and 20-30% of these tumors are aggressive. These aggressive subtypes are characterized by the capacity for invasion of normal brain with frequent and destructive recurrence patterns. Effective local therapies include surgery and radiation, but there is a need for novel molecular targets to improve survival and reduce morbidity for this group or cancer patients. We have recently identified the N-myc down regulated gene 4, NDRG4, protein as being overexpressed in aggressive meningioma, and have proposed to study its role in cell survival, invasion/migration and angiogenesis. We utilized shRNA-containing Lentiviral plasmids to downregulate NDRG4 mRNA and protein expression in two high grade meningioma cancer cell lines, IOMM-Lee and CH157MN. Downregulation resulted in reduction in cell survival, and G2-M cell cycle arrest. Utilizing DNA laddering and Annexin V/APC flow cytometry, we determined that the predominant form of cell death was apoptosis. NDRG4 downregulation also decreased cellular invasion and migration, as determined by a number of assays, including: spheroid migration, linear and radial wound healing assays, Boyden chamber matrigel invasion and 3D invasion assays. To determine the effect of NDRG4 depletion on angiogenesis, we utilized immortalized brain endothelial cells, bEnd.3 cells. We treated the bEnd.3 cells with conditioned media from the NDRG4 depleted IOMM-Lee and CH157MN cells, and the ability to form bEnd.3 capillary-like tubes, to proliferate and to invade was abrogated. NDRG4 is not overexpressed in bEnd.3 cells, and direct NDRG4 depletion had no effect on the cells. This study is significant as it is the first to demonstrate the role of NDRG4 in meningioma tumor biology. NDRG4 is involved in modulating cell proliferation, invasion, migration and angiogenesis in meningioma, and may play a valuable role as a molecular target in its treatment.
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 2282. doi:1538-7445.AM2012-2282