bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1016: Bortezomib (Velcade) induces p27Kip1 expression through S-phase kinase protein 2 degradation in papillary thyroid cancer
Authors: Hussain Azhar , Bu Rong , Bavi Prashant , Ahmed Maqbool , Al-Obaisi Khadija A.S. , Al-Sobhi Saif , Al-Nuaim Abdulrahman , Ahmed Mohammed , Amin Tarek , Uddin Shahab , Al-Kuraya Khwala S. 
Published: June 2012

Abstract
S-phase kinase protein 2 (SKP2), an F-box protein, targets cell cycle regulators including cycle-dependent kinase inhibitor p27Kip1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancers. In this study, we investigated the role of SKP2 and its ubiquitin-proteasome pathway in Papillary Thyroid Cancer (PTC) in a panel of PTC cell lines, a large cohort PTC patient samples and NUDE mouse model using tissue microarray, MTT, flow cytometry and DNA fragmentation assays and western blotting. Our data showed that bortezomib caused a dose-dependent growth inhibition in all cell lines studied. The IC 50 was 83.7nM and 61.4nM for B-CPAP1 and TPC-1 respectively. Cell cycle assay showed that the sub-G1 population of B-CPAP1 cell increased from 4.09% in untreated control sample to 36.74% after 25nM treatment for 2 days and 71.91% after 50nM treatment for 2 days. Further confirmation using FITC-conjugated Annexin V and PI assay showed that apoptotic cell increased form 8.43% in untreated cells to 47.6% and 64.82% after 25nM and 50nM treatment respectively in B-CPAP1 cells and from 12.72% in control to 48.16% and 64.02% in TPC-1 cells, indicating a dose-dependent apoptosis induced in both cell lines. Treatment of PTC cell line cells with bortezomib or expression of small interfering RNA of SKP2 caused down-regulation of SKP2 and accumulation of p27Kip1. Furthermore, treatment of PTC cells with bortezomib caused apoptosis by involving the mitochondrial pathway and activation of caspases-9 and 3, and cleavage PARP. Pretreatment with zVAD-fmk abrogated bortezomib induced apoptosis. In addition, treatment of PTC cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Currently the animal study and data analysis of patient samples are still ongoing. Our preliminary results suggest that SKP2 and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention for treatment of TPC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1016. doi:10.1158/1538-7445.AM2011-1016
Abstract 1018: Regulation of STAT3 by PPARdelta in human hepatocellular carcinoma
Authors: Han Chang , Huang Shuo , Wu Tong 
Published: June 2012

Abstract
Peroxisome proliferator-activated receptor delta (PPARdelta) is a nuclear transcription factor that is recently implicated in tumorigenesis. Previous studies from our lab have shown that PPARdelta activation increases the growth of human hepatocellular carcinoma (HCC) cell lines (Hep 3B, Huh7 and HepG2). The current study was designed to investigate the relationship between PPARdelta activation and STAT3 signaling pathway in human HCC cells. Our data showed that PPARdelta overexpression or activation by its pharmacological ligand (GW501516) significantly increased STAT3-mediated transcriptional activity in Hep3B cells, as determined by luciferease reporter activity assay; this effect is dose-dependent (p&lt;0.01). In contrast, depletion of PPARdelta by its siRNA in Hep3B cells significantly reduced GW501516-induced STAT3 transcriptional activity. PPARdelta overexpression or GW501516 treatment increased the expression of STAT3 protein and induced the translocation of STAT3 from cytosol to nuclei in Hep3B cells. Additionally, PPARdelta overexpression or GW501516 treatment also increased the binding of PPARdelta to STAT3-responsive element through the release of transcriptional repressor Bcl-6. Moreover, overexpression of PPARdelta upregulated the expression of several STAT3 downstream anti-apoptotic molecules including Mcl-1, Suvivin and Bcl-XL. These findings reveal a cross-talk between PPARdelta and STAT3 signaling pathway for human HCC cell growth and such an interaction may play important role in hepatocarcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1018. doi:10.1158/1538-7445.AM2011-1018
Abstract 1021: Bortezomib-mediated inhibition of NF- κB activity leads to induction of apoptosis in activated B-cell like diffuse large B-cell lymphoma
Authors: Bu Rong , Hussain Azhar R. , Ahmed Maqbool , Al-Obaisi Khadija A.S. , Uddin Shahab , Al-Kuraya Khawla S. 
Published: June 2012

Abstract
Diffuse large B-cell lymphoma (DLBCL) is considered to be the most common type of lymphoma in adults, accounting for 30-40% of cases of non-Hodgkin lymphoma, and classified as three distinct subtypes: germinal center B cell-like (GCB)-, activated B cell-like (ABC)-, and primary mediastinal B-cell lymphoma (PMBL). ABC DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic nuclear factor-kappa B (NF-κB) pathway. Yet the implication of NF-κB inhibition in ABC DLBCL need to be further elucidated. Therefore, a panel of ABC DLBCL cell lines was used to examine the effect of bortezomib, a proteasome inhibitor which blocks degradation of phosphorylated IκBα and consequently inhibits NF-κB activity, and small interfering RNA (siRNA) on cell viability, apoptosis and downstream signaling pathway. Our data showed that bortezomib caused a dose-dependent growth inhibition in all cell lines studied. The IC 50 was 3.33 ± 0.29 nM, 2.73 ± 0.32nM, 2.60 ± 0.87nM and 4.35 ± 0.65nM for HBL-1, Riva, Sudhl-2 and OCI-LY3 respectively. Cell cycle assay showed a dose-dependent increase of sub-G1 population of all four cell lines studied after 48 hours treatment, and this increase in sub-G1 population was accompanied by a dose-dependent decrease in the percentage of cells in the G2-M phase indicating the feature of apoptosis. Further experiment using FITC-conjugated Annexin V and PI assay confirmed that apoptotic cell increased in a dose-dependent manner in all cell lines after 48 hour treatment. Moreover, the electrophoretic mobility shift assay showed that bortezomib treatment inhibited constitutive nuclear NF-κB in ABC cell lines. Furthermore, treatment of ABC cell lines with bortezomib or expression of small interfering RNA of NF-κB also down-regulated expression of NF-κB-regulated gene products, such as IκBα, Bcl-2, Bcl-Xl, XIAP and Survivin leading to apoptosis via the mitochondrial apoptotic pathway. Altogether, these results suggest that NF-κB may be a potential target for therapeutic intervention in DLBCL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1021. doi:10.1158/1538-7445.AM2011-1021
Abstract 103: Array-based DNA methylation profiling of oral squamous cell carcinoma with lymph node invasion and clinical implications
Authors: Huang Wei-Li , Chang Shu-Hao , Kao Shou-Yen , Su Pei-Fen 
Published: June 2012

Abstract
Background: Oral squamous cell carcinoma (OSCC) is the sixth common cancer and is highly mortal due to tumor recurrence and metastasis. Invasion of tumor cells into lymph nodes is one of the characters of regional metastasis. Here we assessed whether epigenetic modification of DNA methylation is correlated to OSCC regional metastasis and evaluated the potential clinical implications of DNA methylation-based biomarker.
Methods: A case-control study of OSCC patients with lymph node invasion (N=8), OSCC patients without lymph node invasion (N=6), and normal oral tissues (N=2) was performed. To characterize aberrant DNA methylation in OSCC tumors with regional metastasis at diagnosis, Illumina infinium beadsarrays containing 27,578 CpG loci which cover 14,475 genes were applied. The genomic DNA of test samples was individually bisulfite-converted and subjected to beadsarray analysis. β value, the indicator of methylation status of each tested CpG locus, was derived with proper normalization.
Results: Methylation β values allocated tested tissues into regional metastatic tumor, non-metastatic tumor, and control groups. A cluster of 111 CpG loci was selected based on the difference between the mean β value of OSCC tumors with and without regional metastasis. There were 69 loci and 42 loci that were hypermethylated (Δβ value ≫ 0.2) and hypomethylated (Δβ value ≪ −0.2), respectively, in OSCC with regional metastasis. Differentially methylated genes appeared to be mainly related to organ development, cell death, cell signaling, behavior, nucleic acid metabolism, and molecular transport. Several genes were further investigated for their methylation statuses by genomic bisulfite sequencing and DNA methyltransferase inhibitor reactivation in oral carcinoma cell lines with or without invasiveness. Characterization the association of hypermethylation of metastatic-associated genes and clinical pathological variables, we found combination of the hypermethylation status of a candidate gene and p16INK4A improved the prediction of lymph node invasiveness (p=0.003) and survival rate (p=0.010). Our results show the feasibility of this beadsarray analysis to identify aberrant methylation of metastatic-associated genes in OSCC as well as potential risk assessment application. The cohort for the risk assessment assay will be increased and the biological activities of candidate genes in carcinogenesis will be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 103. doi:10.1158/1538-7445.AM2011-103
Abstract 1034: A natural inhibitor of c-Jun N-terminal kinase 1
Authors: Yao Ke , Cho Yong-Yeon , Chen Hanyong , Song NuRy , Liu Kang-Dong , Wen Weihong , Bode Ann M. , Dong Zigang 
Published: June 2012

Abstract
The c-Jun N-terminal kinases (JNKs) pathway plays a important role in many physiological processes including cell proliferation, survival, death, DNA repair and metabolism induced by a variety of stress signals and pro-inflammatory stimuli. The JNK proteins are encoded by three genes, jnk1, jnk2, jnk3. The protein products of jnk1 and jnk2 are found in all cells and tissues, whereas the JNK3 protein is found primarily in the brain, but is also found in the heart and the testes. The unequal expression of the different isoforms of JNK is possibly determined by some unique characteristics. Each JNK appears to have a distinct function in cancer, asthma, diabetes, and Parkinson's disease. Recent studies demonstrate that JNK1 is a key contributor for the serine phosphorylation of the IRS-1. Several other studies also demonstrated the importance of JNK1, but not JNK2, in lung fibrosis and gastric cancer. We have identified a novel flavonoid isolated from natural sources, herein referred to Compound-A, that suppressed JNK1 activity, with no effect on JNK2 in vitro. At 10 μM, Compound-A specifically inhibited JNK1 by about 50%. We also found that compound-A inhibits UVB-induced c-Jun phosphorylation in a cell culture system. In contrast to SP600125, a non-selective JNKs inhibitor that binds to the ATP active site, compound-A appears to target the protein-protein interaction between JNK1 and its binding proteins, including the JNK-interacting protein-1(JIP1) rather than the ATP binding site. In a computer simulation model, compound-A complexed with JNK1, but not JNK2, and formed strong hydrogen bonding at Glu329. Glu329 is a key residue for the JNK complex with JIP1. This interaction induces a hinge motion between the JNK N- and C-terminal domains and decreases the affinity of the kinase and ATP. These results demonstrate that compound-A is a selective JNK1 inhibitor. In humans, JNK1 play a key role in obesity-induced type 2 diabetes mellitus and the absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and an enhanced insulin receptor signaling capacity in mouse obesity models. Therefore, we suggest that because of JNK1's critical role in diabetes, compound-A might have therapeutic potential against this devastating disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1034. doi:10.1158/1538-7445.AM2011-1034
Abstract 1037: Effects of stimulary GTP binding protein on the expression of histone deacetylase 6 and 8
Authors: Lim Jeong Ah , Park Ji-Yeon , Juhnn Yong-Sung 
Published: June 2012

Abstract
Stimulatory heterotrimeric GTP-binding protein (Gαs protein) is one of the four families of α subunit in G proteins, and stimulates cAMP production. Gαs protein is involved in many cellular signaling pathways, and regulates various cellular metabolism and gene expression. Histone deacetylases (HDACs) are the enzymes that perform epigenetic regulation of gene expression by removing of acetyl groups from histones. The HDAC family is composed of 18 proteins, and belongs to two major families: the zinc-dependent HDACs (class I, II, and IV), and NAD-dependent (sirtuins-like class III). Human class I HDACs include HDAC1, 2, 3 and 8, and human class II HDACs include HDAC4, 5, 6, 7, 9 and 10.
Thus we analyzed the effect of Gαs on the expression of HDAC isoforms and its underlying molecular mechanism in H1299 human lung cancer cells. We found the expression of HDAC6 and HDAC8 isoforms were increased by the overexpression of the constitutively active Gαs proteins (GαsQL). The levels of HDAC6 and HDAC8 mRNA were increased following GαsQL expression. Treatment with forskolin also increased HDAC6 and HDAC8 levels, and treatment with H89 inhibited the increase in HDAC6 and HDAC8 levels induced by GαsQL. Furthermore, prostaglandin E2, a Gαs activating signal, also increased in HDAC8 levels. The increased expression of HDAC6 through this signaling pathway caused a decrease in acetylation level of α-tubulin. From these results, it is concluded that Gαs-cAMP signaling pathway augments HDAC6 and HDAC8 expression in H1299 lung cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1037. doi:10.1158/1538-7445.AM2011-1037
Abstract 1038: Regulation of cyclin A by FoxO3a drives proliferation in anaplastic thyroid carcinoma
Authors: Marlow Laura , von Roemeling Christina , Zhang Yilin , Cooper Simon , Rohl Stephen , Tun Han , Storz Peter , Smallridge Robert , Copland John A. 
Published: June 2012

Abstract
The Forkhead transcription factor, FoxO3a, is a known suppressor of primary tumor growth and is negatively regulated by growth factors via phosphorylation and mislocalization from the nucleus to the cytoplasm. Here we show for the first time that FoxO3a is nuclear in anaplastic thyroid carcinoma (ATC) and it transcriptionally upregulates cyclin A thereby promoting tumor growth in human ATC cells. Silencing FoxO3a in ATC cell lines leads to down-regulation of cyclin A mRNA and protein while over-expression of FoxO3a leads to upregulation of cyclin A protein. Transient co-transfection of cyclin A promoter linked to luciferase with FoxO3a leads to enhanced luciferase activity, which can be ablated when mutating the FoxO3a site on the cyclin A promoter. This combined data implicates an entirely novel function for FoxO3a in modulating cancer progression by promoting cell cycle progression and tumor growth. ATC is a poorly differentiated carcinoma with average survival upon diagnosis of 3–4 months with 99% lethality, notably the most aggressive and deadliest cancers known. This data also suggest that any therapies under development to inactivate FOXO3a may be effective at blocking tumor expansion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1038. doi:10.1158/1538-7445.AM2011-1038
Abstract 1041: Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung
Authors: Magnussen Annika , Karlsson Christina , Söderkvist Peter , Karlsson Mats G. , Thunell Lena K. 
Published: June 2012

Abstract
The aim of the study was to investigate how alterations in the PI3K pathway correlate with the non-small cell lung cancer subtypes squamous cell carcinoma (SSC) and adenocarcinoma (ADCA). We analyzed copy number variation (CNV) and protein expression of the newly identified phosphatase INPP4B, protein expression of pAkt, PDPK1 and PTEN as well as mutational status of PIK3CA and PTEN in 180 lung cancer cases. Nineteen % of all cases displayed loss of INPP4B copy whereas 47% lacked expression. Both CNV and expression analyses showed a correlation between loss of INPP4B and the squamous subtype (RR = 1.44, p = 0.06; RR = 1.86, p = 0.00003). Elevated level of pAkt expression was seen in 63% of all cases and also correlated specifically to SCC (RR = 1.71, p = 0.001). PDPK1 was expressed in 70% of all cases, more in male than female patients, but no difference between the tumor subtypes. Regarding PTEN, 50% of all cases displayed loss of expression, of which seven cases were identified with mutations in the phosphatase or C2 domains. We detected nine cases (5%) of PIK3CA mutations, all identified as the E545K hot spot mutation in the helical domain, all except one in SCC (RR = 1.69, p = 0.05). When analyzing all PI3K pathway components together, we show that patients with at least one alteration in the PI3K pathway are twice as likely to have SCC, than ADCA (RR = 2.01, p = 0.02). Interestingly, we also found a strong correlation between high pAkt expression and PTEN expression, which we speculate can be explained by a feedback-loop via EGR1 and ARF recently proposed by Yu et al, 2009. As comparison, we also analyzed MAPK pathway genes, where we identified fifteen KRAS mutations (8%) and one BRAF mutation (1%), significantly associated to ADCA. The intermediate insulin receptor substrate 1 (IRS-1) is involved in activation of both the PI3K and MAPK pathways and we were interested in studying the Gly972Arg polymorphism previously shown to be associated with prostate, colon and breast cancer. However, we could not detect any associations to any subgroup. In conclusion, we show here that several components of the PI3K pathway, alone and in combination, are correlated to development of squamous cell carcinoma of the lung.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1041. doi:10.1158/1538-7445.AM2011-1041
Abstract 1042: Balance between several phosphatases is crucial for statin- and ATP-induced depletion of nuclear pAkt in prostatic cancer cells
Authors: Ghalali Aram , Högberg Johan , Stenius Ulla 
Published: June 2012

Abstract
We have previously shown that cholesterol-lowering drugs, statins, or extracellular ATP, induce a complex and coordinated response in insulin-stimulated non-small cell lung cancer cells (A549), leading to depletion of nuclear phosphorylated Akt (pAkt). The response involved activation of protein/lipid phosphatases PTEN, PHLPP1 and −2, PP2A and calcineurin (J Biol Chem, 285, 27900, 2010). As Akt might be critical for prostatic cancer (PC) development and statins may prevent aggressive PC the effects of statins and ATP on Akt signaling in PC cells was studied. It was found that atorvastatin in micromolar concentrations decreased constitutive levels of pAkt in DU145 and 22RV1 cells. The effect was associated with a decreased phosphorylation of downstream targets of pAkt. Furthermore, we found that insulin-induced pAkt was inhibited by atorvastatin. Our previous data indicated that PTEN and PHLPP are essential for depletion of nuclear pAkt. In line with this no down-regulation of nuclear Akt and its downstream targets was induced by statins in PTEN deficient LNCaP cells. However, the statin-induced down-regulation of nuclear Akt was restored when cells were transfected for PTEN. We also transfected PTEN deficient PC3 cells with PTEN. However, in this cell line PTEN transfection did not restore the capacity of statins to deplete nuclear pAkt. Instead, we found that in PC3 cells the PTEN transfection lowered levels of PHLPP2 and PHLPP1. When the cells were transfected for both PTEN and PHLPP2 the capacity of statins to deplete nuclear pAkt was restored in PC3 cells. The crosstalk between PHLPP and PTEN was further studied in LNCap, PC3, 22RV1 cells and it was found that increasing PTEN levels depressed the levels of PHLPP 1 and 2 and vice versa. The similar cross talk was also observed between PHLPP1 and 2. These data indicate that a balance between different phosphatases is essential for statin-induced depletion of nuclear Akt. This might be due to the fact that formation of complexes between Akt and different phosphatases is needed for the depletion of nuclear pAkt. Our data suggest that a well-controlled balance between essential phosphatases is needed for nuclear pAkt depletion. This balance seems disturbed in many prostate cancer cell lines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1042. doi:10.1158/1538-7445.AM2011-1042