bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 22: Differential IGF-II response of AA and CA normal breast cell lines to prolactin treatment
Authors: Calderon Teleka , León Marino De , De León Daisy D. 
Published: August 2012

Abstract
African-American (AA) breast cancer patients have lower survival compared with Caucasian-American (CA) patients. This survival disparity is significant in view of the lower incidence of breast cancer among AA. Lower incidence of breast cancer is associated with parity and lactation in young women. Lactation's protective effect is mediated by fatty-acid binding protein 3 (FABP3), a protein that promotes differentiation of breast epithelial cells. We have demonstrated that AA normal women below 50 years have lower FABP3 levels as compared to CA women (p = 0.030). FABP3 is a protective tumor suppressor that increases during pregnancy and lactation, in response to the lactation hormone prolactin (PRL). PRL effects on the breast are mediated by IGF-II. Thus, we propose that PRL treatment of normal epithelial breast cell lines would increase IGF-II to promote differentiation, increase FABP3, and decrease FABP5. FABP5 is associated with metastasis and may compensate for FABP3 decrease. We treated MCF10A (CA) and AG11132 (AA) normal breast epithelial cell lines with recombinant human PRL (0-200 ng/ml) for 24 hours. Cell lysates were examined for protein and mRNA levels of IGF-II, FABP3, and FABP5. In MCF10A cells, PRL stimulated an increase in protein levels of IGF-II (p=0.044), and a decrease in protein levels of FABP5 (p=0.044). Protein levels of FABP3 significantly decreased with increasing PRL concentration (p=0.030). IGF-II mRNA levels also increased at 50 and 200 ng/ml PRL (2.59 and 2.58 fold, respectively). In AG11132 cells, protein levels of FABP3 significantly increased with increasing PRL concentration (p=0.016). IGF-II and FABP5 mRNA levels increased significantly at 10 ng/ml PRL (49.91 and 2.13 fold, respectively); however, no corresponding changes were seen in protein levels. Though both cell lines respond to PRL treatment, only the MCF10A line displays increased IGF-II and decreased FABP5, which are protective changes in normal mammary cells. FABP3 levels decreased in MCF10A cells at higher PRL concentrations; this may be due to untreated MCF10A cells expressing significantly more FABP3 and prolactin, relative to AG11132 cells. The higher levels of PRL and FABP3 in untreated MCF10A cells indicate that they are more differentiated and thus require less PRL stimulation, relative to the AG11132 cells, to achieve a differentiated state. The dissimilar responsiveness of these cell lines to PRL may suggest decreased protection against breast carcinogenesis in AA patients, and may help us to further understand this health disparity.
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 22. doi:1538-7445.AM2012-22
Abstract 2214: COUP-TFII suppresses NFκB activation in endocrine-resistant breast cancer cells
Authors: Litchfield Lacey M. , Klinge Carolyn M. 
Published: August 2012

Abstract
COUP-TFII is an orphan nuclear receptor that can function as either a transcriptional activator or repressor. We have previously shown that COUP-TFII expression is reduced in tamoxifen-resistant LCC9 breast cancer cells and that overexpression of COUP-TFII restored the ability of tamoxifen to inhibit cell proliferation. An increase in NFκB activity and p65/RELA level has been reported in endocrine-resistant breast cancer cells. Because NFκB activation results in increased expression of anti-apoptotic and pro-proliferative genes, increased NFκB signaling promotes the survival of cancer cells. The goal of the current study was to further elucidate the mechanism by which COUP-TFII enables cells to maintain endocrine sensitivity and to determine if COUP-TFII modulates NFκB activity in tamoxifen-resistance. To examine whether COUP-TFII can suppress NFκB activity, MCF-7 (tamoxifen-sensitive, TAM-S) and LCC9 (tamoxifen-resistant, TAM-R) breast cancer cells were transfected with a NFκB luciferase reporter and treated with TNFα to activate NFκB. Cotransfection with COUP-TFII reduced NFκB activity in both TAM-S and TAM-R cell lines. Knockdown of COUP-TFII with siRNA led to an increase in p65 expression; conversely, COUP-TFII overexpression led to a suppression of p65 expression. COUP-TFII overexpression also reduced TNFα-induced endogenous NFκB target gene expression. Preliminary data also suggests that suppression of NFκB activation by COUP-TFII leads to a reduction in cell viability in MCF-7 and LCC9 cells in response to tamoxifen and TNFα treatment. This indicates a novel role for COUP-TFII in suppression of NFκB activity which may explain the ability of COUP-TFII to promote tamoxifen-sensitivity. COUP-TFII may be both a useful biomarker to predict tamoxifen-sensitivity as well as a target to restore endocrine sensitivity to resistant 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 2214. doi:1538-7445.AM2012-2214
Abstract 2223: Epigenetic silencing of ribosomal RNA genes by Mybbp1a
Authors: Liu Hsuan , Tan Bertrand , Yung Benjamin Y.-M. 
Published: August 2012

Abstract
Transcription of the ribosomal RNA gene repeats by Pol I occurs in the nucleolus and is a fundamental step in ribosome biogenesis and protein translation. Due to tight coordination between ribosome biogenesis and cell proliferation, transcription of rRNA and stable maintenance of rDNA clusters are thought to be under intricate control by intercalated mechanisms, particularly at the epigenetic level. Here we identify the nucleolar protein Myb-binding protein 1a (Mybbp1a) as a novel negative regulator of rRNA expression. Suppression of rDNA transcription by Mybbp1a was linked to promoter regulation as illustrated by its binding to the chromatin around the hypermethylated, inactive rDNA gene promoters. Our data further showed that downregulation of Mybbp1a abrogated the local DNA methylation levels and histone marks associated with gene silencing, and altered the promoter occupancy of various factors such UBF and HDACs, consequently leading to elevated rRNA expression. Mechanistically, we propose that Mybbp1a maintains rDNA repeats in a silenced state while in association with the negative epigenetic modifiers HDAC1/2. Results from our present work reveal a previously unrecognized co-repressor role of Mybbp1a in rRNA expression. They are further consistent with the scenario that Mybbp1a is an integral constituent of the rDNA epigenetic regulation that underlies the balanced state of rDNA clusters.
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 2223. doi:1538-7445.AM2012-2223
Abstract 223: Oncogenic resistance of Akt kinases to dephosphorylation through an ATP-dependent molecular switch
Authors: Chan Tung 
Published: August 2012

Abstract
The serine/threonine Akt protein kinases (Akt1, Akt2 and Akt3) affect multiple cellular functions associated with “hallmark” properties of cancer, such as cell growth and survival, differentiation, metabolism and migration. Hyperphosphorylation of a threonine residue (Thr308 in Akt1) in the activation loop of Akt kinases is a prerequisite for the deregulated Akt activity frequently that is observed in neoplasia. Conversely, phosphatases including type 2A serine/threonine phosphatase (PP2A), reverse Akt phosphorlyation and activity. Here, we describe a new layer of control of Akt phosphorylation that points to ATP binding pocket occupancy as a means to decelerate Akt dephosphorylation. We show that targeting Akt kinases to the cell membrane markedly reduces the ability of phosphatases to dephosphorylate Thr308. This effect depends on the occupancy of the ATP binding pocket by either ATP or ATP competitive Akt kinase inhibitors (A443654 or G690693). To reconstitute this effect, we use purified phosphatases and Akt proteins to show that ATP markedly inhibits the dephosphorylation of phospho-Thr308 in vitro. Mutational analysis reveals that Arg273 in Akt1 and the corresponding Arg274 in Akt2 are essential for shielding Thr308 against dephosphorylation. While the binding of ATP and several ATP “mimic” inhibitors, ATP-γS, A-443654 and G690693 inhibits Akt dephosphorylation, the binding of other closely related molecules, ADP, ADPβS and isoquinoline sulphonamide (IQS, Ki 0.23uM) does not block dephosphorylation, suggesting unique determinants in the γ-phosphate of ATP that regulate Akt dephosphorylation. These results suggest that occupancy of the ATP-binding pocket of Akt kinases stabilizes a conformational state of the Akt kinase domain that restricts phosphatase access to phospho-Thr308, thereby sustaining Akt phosphorylation. Finally, we determine that phosphorylated Akt kinases in untransformed cells are subject to rapid dephosphorylation. However, in several cancer-derived cell lines, phosphorylated Akt kinases are highly resistant to dephosphorylation and the resistance depends on ATP-occupation. In addition, dephosphorylation resistance provides a mechanistic explanation for the ‘paradoxical’ phosphorylation of Akt previously described for ATP competitive inhibitors, A443654 and G690693. Also, dephosphorylation resistance may be the converging point of the oncogenic signals that induce Akt hyperactivation. Exploration of structures and amino acids involved in this process may hold the key to developing the next generation of pharmacological agents that could promote normal Akt physiology while inhibiting cancer cells for more positive results in cancer therapy.
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 223. doi:1538-7445.AM2012-223
Abstract 2233: IKBKE activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 to sustain malignant transformation
Authors: Guo Jianping , Coppola Domenico , Cheng Jin Q. 
Published: August 2012

Abstract
Serine/threonine kinase Akt regulates key cellular processes such as cell growth, proliferation, and survival. Activation of Akt by mitogenic factor depends on phosphatidylinositol 3-kinase (PI3K). Here, we report that IKBKE activates Akt in response to inflammatory agent but not growth factor stimuli through a PI3K-independent pathway. Depletion of IKBKE inhibits basal and inflammatory factor-stimulated Akt activation. IKBKE directly phosphorylates Akt-Thr308 and -Ser473 independent of plecstrin-homology (PH) domain. IKBKE activation of Akt was not affected by inhibition of PI3K, knockdown of PDK1 or mTORC2 complex. Further, this activation could be inhibited by Akt inhibitors MK-2206 and GSK690693 but not the compounds (perifosine and triciribine) targeting PH domain of Akt. Expression of IKBKE largely correlates with activation of Akt in breast cancer. Moreover, inhibition of Akt suppresses IKBKE oncogenic transformation. These findings indicate that IKBKE is an Akt-Thr308 and -Ser473 kinase and directly activates Akt independent of PI3K, PDK1 and mTORC2. Our data also suggest that Akt inhibitors targeting the PH domain have no effect on the tumours in which hyperactive Akt is resulted from elevated IKBKE.
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 2233. doi:1538-7445.AM2012-2233
Abstract 2237: Analysis of the PI3K/Akt signaling pathway in neuroblastoma shows stage dependent expression of PI3K isoforms
Authors: Fransson Susanne M. , Abel Frida , Eriksson Helena , Kogner Per , Martinsson Tommy , Ejeskär Katarina 
Published: August 2012

Abstract
The phosphoinositide-3 kinase (PI3K) pathway plays a critical role in cancer cell growth and survival and has also been implicated in the development of the childhood cancer neuroblastoma. In neuroblastoma high mRNA expression of the PI3K catalytic isoform PIK3CD is associated to favorable disease. Yet, activation of Akt is associated with poor prognosis. Since the contribution of the numerous members of this pathway to neuroblastoma pathogenesis is mainly unknown, genes of the PI3K/Akt pathway were analyzed at mRNA and/or protein level. Out of 88 studied genes, five (PRKCZ, PRKCB1, EIF4EBP1, PIK3RI and PIK3CD) showed lower mRNA expression and one (PDGFRA) showed higher expression in aggressive compared to favorable tumors. PIK3R1 encodes p85α, the regulatory subunit of the Type IA PI3K and is suggested to have tumor suppressing functions and in neuroblastoma, high expression of PIK3R1 is strongly correlated to overall patient survival. p110α, encoded by PIK3CD was preferentially expressed in favorable neuroblastomas while p110α (encoded by PIK3CA) was mainly found in patients with advanced disease which also showed higher levels of both p-Akt T308 and p-Akt S473. Further more, levels of p-Akt T308 showed inverse correlation to Pten levels although no significant difference in protein levels of Pten could be detected comparing aggressive and favorable neuroblastoma tumors. The pattern of p110alpha and p110delta indicates complementary functions in Akt activation depending on neuroblastoma stage and evaluation of the expression of the different PI3K isoforms in each neuroblastoma patient could be crucial for the success of treatment with PI3K isoform specific inhibitors.
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 2237. doi:1538-7445.AM2012-2237
Abstract 224: TOPK phosphorylation of MKP1 prevents solar ultraviolet irradiation-induced inflammation by inhibiting p38 signaling
Authors: Li Shengqing , Zhu Feng , Zykova Tatyana , Kim Myoung Ok , Bode Ann M. , Peng Cong , Ma Weiya , Dong Zigang 
Published: August 2012

Abstract
Solar ultraviolet (UV) irradiation is a major environmental factor that causes DNA damage, inflammation, and skin cancer. T-LAK cell-originated protein kinase (TOPK) is widely expressed in both normal and cancer cells and functions to inhibit apoptosis and promote carcinogenesis. However, its function in inflammation is not known. The p38 MAPK signaling pathway plays an important role in solar UV light-induced inflammation. The phosphorylation level of p38 was reported to be up-regulated after transfection of the TOPK gene into COS-7 cells. We found that the phosphorylation level of p38α was increased in TOPK-/- mouse embryonic fibroblasts (MEFs) compared with TOPK+/+ MEFs after stimulation with solar UV light. Our observations unveil a novel role for TOPK. We found that TOPK negatively regulated the activity of p38α by phosphorylating the p38α-specific phosphatase MKP1 and enhancing the stability of MPK1. Notably, the absence of TOPK in mice resulted in a striking increase in skin inflammation. Therefore, we conclude that TOPK has a protective function in solar UV light-induced inflammation.
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 224. doi:1538-7445.AM2012-224
Abstract 2247: Torin2 targets mTOR activity and induces apoptosis in DLBCL cells
Authors: Uddin Shahab , Bu Rong , Thangavel Saravanan , Hussain Azhar R. , Al-Kuraya Khawla S. 
Published: August 2012

Abstract
The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, acts as a master switch for cellular anabolic and catabolic processes, regulating the rate of cell growth and proliferation. Dysregulation of the mTOR signaling has been found in many human cancers, including epithelial ovarian cancer, breast cancer, prostate cancer and lung cancer. mTOR has been shown to activate the PI3-kinase/AKT survival pathway and understanding the interplay among signaling molecules in the PI3K/Akt/mTOR pathway is of utmost importance. Two distinct mTOR complexes; mTORC1 and mTORC2, have been identified. mTORC1 is downstream of Akt, sensitive to rapamycin inhibition, and controls cap-dependent protein translation. In contrast, mTORC2 is directly upstream of Akt and is resistant to rapamycin. In order to successfully inhibit mTOR activity, mTORC1 and 2 have to be simultaneously inhibited at the same time to effectively induce apoptosis. The role of mTOR in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. Therefore, we examined the effect of a new generation mTOR inhibitor (Torin2) on a panel of DLBCL cell lines. We found that Torin2 treatment inhibited cell viability and induced apoptosis in DLBCL cell lines in a dose dependent manner with an IC50 of 53nM. In addition, Torin2 also activated the mitochondrial apoptotic pathway by causing changes in the mitochondrial membrane potential, activation of caspase-9 and -3 and cleavage of PARP. Finally, Torin2 treatment of DLBCL cell lines also down-regulated the expression of inhibitor of apoptosis proteins (IAPs); XIAP and Survivin in a dose dependent manner. As mTOR has been shown to activate down stream targets such as p70S6 as well as up-stream targets such AKT, we will further investigate the effect of Torin2 treatment on these targets. In addition, we will also determine whether Torin2 treatment causes disruption of cross talk between mTOR and PI3-kinase/AKT pathways. These studies will give us an insight on the molecular relationship between these survival pathways and may detect newer survival molecules that can be targeted for efficient treatment of these cancers.
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 2247. doi:1538-7445.AM2012-2247
Abstract 2254: FIP200 regulation by hypoxia in brain endothelial cells
Authors: Kar Niladri S. , Tipps Russell , Yang Haifeng , Gladson Candece L. 
Published: August 2012

Abstract
Angiogenesis is a prominent characteristic of glioblastoma tumors. Hypoxia occurs in glioblastoma tumors and is thought to promote angiogenesis largely through a HIF-dependent mechanism. The effect of hypoxia on survival proteins expressed by endothelial cells (ECs), such as focal adhesion kinase interacting protein of 200kDa (FIP200, also known as RB1CC1), has received little attention. We recently reported that the expression of FIP200 is increased in the angiogenic endothelial cells of glioblastoma tumors. FIP200 can promote cell survival through its promotion of autophagy, or by inhibiting Pyk2 activation and Pyk2-mediated apoptosis. We found that hypoxia upregulated FIP200 protein expression and that this upregulation of FIP200 was independent of the downregulation of ARNT, suggesting it was HIF-independent. We then examined the post-translational modification of FIP200 and whether it was differentially regulated in hypoxia. We found that FIP200 is degraded in the proteosome in normoxia, and that there may be alterations in the proteosomal degradation pathway in hypoxia that contribute, in part, to the elevated FIP200 protein level. Understanding the mechanism for the increased expression of FIP200 in hypoxia may provide future therapeutic targets for new anti-angiogenic therapy.
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 2254. doi:1538-7445.AM2012-2254
Abstract 2258: Cadmium induces autophagy through ROS-dependent activation of the LKB1-AMPK signaling in skin epidermal cells
Authors: Son Youngok , Shi Xianglin 
Published: August 2012

Abstract
Cadmium is a toxic heavy metal which is environmentally and occupationally relevant. The mechanisms underlying cadmium-induced autophagy are not yet completely understood. The present study shows that cadmium induces autophagy, as demonstrated by the increase of LC3-II formation and the GFP-LC3 puncta cells. The induction of autophagosomes was directly visualized by electron microscopy in cadmium-exposed skin epidermal cells. Blockage of LKB1 or AMPK by siRNA transfection suppressed cadmium-induced autophagy. Cadmium-induced autophagy was inhibited in dominant-negative AMPK-transfected cells, whereas it was accelerated in cells transfected with the constitutively active form of AMPK. mTOR signaling, a negative regulator of autophagy, was downregulated in cadmium-exposed cells. In addition, cadmium generated reactive oxygen species (ROS) at relatively low levels, and caused poly(ADP-ribose) polymerase-1 (PARP) activation and ATP depletion. Inhibition of PARP by pharmacological inhibitors or its siRNA transfection suppressed ATP reduction and autophagy in cadmium-exposed cells. Furthermore, cadmium-induced autophagy signaling was attenuated by either exogenous addition of catalase and superoxide dismutase, or by overexpression of these enzymes. Consequently, these results suggest that cadmium-mediated ROS generation causes PARP activation and energy depletion, and eventually induces autophagy through the activation of LKB1-AMPK signaling and the down-regulation of mTOR in skin epidermal 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 2258. doi:1538-7445.AM2012-2258