bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2931: Zerumbone, a phytochemical from asian ginger inhibits JAK/STAT pathway, growth, apoptosis and increase taxol sensitivity of hormone refractory prostate cancer cells
Authors: Chakraborty Arup , Jorvig Jessica 
Published: June 2012

Abstract
Objectives: Prostate cancer (PCa) is the most common cancer incidence and the second cancer death in U.S. men. In 2010, an estimated 217,730 new cases of PCa will be diagnosed, and 32,050 people will die from the disease in USA alone. IL-6 is strongly associated with malignant phenotype of PCa. IL-6 potently activates signal transducers and activators of transcription 3 (STAT3), a member of the family of latent cytoplasmic transcription factors that transmit signals from the cell membrane to the nucleus. STAT3 activation is known to promote tumor cell proliferation, survival, angiogenesis, and metastasis in vivo. In PCa, IL-6 strongly promotes mitogenic and angiogenic signaling through phosphorylation of Jak2 and then STAT3. Zerumbone, a relatively new anticancer component isolated from Zingiber zerumbet Smith has not been previously evaluated for prostate cancer.
AIM: 1. Determine the activity and mechanism of zerumbone on hormone refractory prostate cancer cells. 2. Evaluate the combined effect of taxol (paclitaxel) with zerumbone in killing hormone-refractory prostate cancer cells.
Methods and Results: The apoptosis and cytotoxic effect of zerumbone were determined by PARP cleavage (western blot) and MTS assay in DU145 cells. Zerumbone induced cytotoxicity with IC50 = 24 µM and significant PARP cleavage. Zerumbone (25 μM) potently inhibited constitutively activated Jak2/STAT3 phosphorylation and IL-6-stimulated STAT3 phosphorylation in DU145 cells as determined by western blots. Zerumbone (25 μM) also blocked expression of STAT3 dependent antiapoptotic proteins Bcl-xL. Interestingly, zerumbone even at a higher dose like 50uM has no effect on p65 subunit phosphorylation of NFkB and MAP kinase phosphorylation indicating a relative specificity. Next, we determined the combined effect of zerumbone and taxol in DU145 cells. Zerumbone as low as 10µM (4% cytotoxicity) synergistically increased cytotoxicity of taxol (5 nM, 7% cytotoxicity) to 25% cytotoxicity when combined. Zerumbone (10µM) also decreased IC50 of taxol from 12 nM to 7 nM.
Conclusion: We showed that zerumbone is a potential therapeutic agent in prostate cancer by effectively blocking Jak2/STAT3-mediated signaling pathways and in addition, zerumbone combining with taxol based cytotoxic therapies may offer encouraging strategies for combating hormone-refractory prostate cancers.
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 2931. doi:10.1158/1538-7445.AM2011-2931
Abstract 2940: A role for PAX8 in promoting tumor cell type-specific proliferation through positively regulating E2F1 transcription and stabilizing RB protein
Authors: Eccles Mike R. , Li Caiyun G. , Nyman Jennifer E. , Braithwaite Antony W. 
Published: June 2012

Abstract
The PAX proteins are tissue-specific developmental regulators required for fetal development. In most cases, PAX expression is silenced post-natally, although it is maintained in some adult tissues. Several PAX proteins interact with RB, a key protein involved in cell cycle regulation. The phosphorylation of RB leads to the mobilization of the master regulator of cell cycle progression, E2F1. It is presently unknown how the growth and differentiation of a tissue is coordinated in a tissue-specific manner with the regulation of the cell cycle in order to facilitate terminal differentiation, or how this process might be disrupted in cancer. PAX gene dysregulation is observed in many cancer types with PAX8 being frequently expressed in renal cell carcinoma (RCC), bladder, ovarian and thyroid cancer cell lines. We investigated the effect on the RB-E2F1 pathway of knocking-down PAX8 using siRNAs in cell lines corresponding to these four cancer types. Knockdown of PAX8 led to a striking reduction in E2F1 mRNA and protein in cancer cell lines, as well as a reduction in levels of E2F1 target genes, including cyclin A2 (CCNA2) and CDC6, induction of a G1/S cell cycle arrest, the onset of cellular senescence, and a proteosome-dependent destabilization of RB protein, with RB1 mRNA levels remaining unaffected. Using ChIP and luciferase reporter assays we showed that PAX8 binds to and transcriptionally regulates the E2F1 promoter. These data suggest that the expression of PAX8 is associated with transcriptional activation of E2F1 and stabilization of RB protein in cancer cell lines. During development in normal tissues we presume that expression of PAX8 coordinates cell proliferation with tissue-specific growth. In cancer, however, the expression of PAX8 continues unabated, and PAX8 silencing leads cancer cells to undergo cell cycle arrest, and subsequently to become senescent.
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 2940. doi:10.1158/1538-7445.AM2011-2940
Abstract 2954: The transient receptor potential V6 (TRPV6) calcium channel in breast cancer cell lines and clinical breast cancer tissues
Authors: Peters Amelia , Simpson Peter , Bassett Jonathon , Lakhani Sunil , Roberts-Thomson Sarah , Monteith Gregory 
Published: June 2012

Abstract
TRPV6 is an important calcium channel, which is highly selective for Ca2+ and has high basal activity. In prostate tumors TRPV6 over-expression is linked to enhanced invasiveness and proliferation. While some studies have demonstrated that TRPV6 is over-expressed in clinical breast cancer samples and studies from our laboratory have shown that TRPV6 mRNA is up-regulated in a sub-set of breast cancer cell lines, a link between TRPV6 expression and breast cancer aggressiveness has not been demonstrated. Furthermore, the mechanism for the over-expression of TRPV6 in breast cancer is unknown. To explore TRPV6 gene amplification as a possible mechanism for over-expression, we used a real-time PCR copy number assay and identified a sub-set of breast cancer cells lines that exhibited increased TRPV6 gene copy number. To assess the clinical relevance of this finding, we initially used a high throughout, clinically driven approach to examine TRPV6 gene amplification in breast tumors. Our findings showed that the mechanism of TRPV6 over-expression is due to, at least in part, gene amplification and that gene amplification may be pronounced in breast cancer subtypes with a poor prognosis. In clinical breast tumor samples, microarray based comparative genomic hybridization (aCGH) showed that the TRPV6 gene region (7q34) is gained in 0/16 invasive lobular carcinomas and in 11/35 high grade invasive ductal carcinomas. When stratified by estrogen receptor status, 7/13 estrogen receptor negative, high grade invasive ductal carcinomas harbored a gain in this region. To determine whether the copy number increase observed at the gene region 7q34 specifically corresponded with amplification of the TRPV6 gene, we performed chromogenic in situ hybridization (CISH) using a probe specific for the TRPV6 gene and a breast cancer tissue microarray. Our findings suggest that a sub-set of breast cancers may be characterized by TRPV6 gene amplification.
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 2954. doi:10.1158/1538-7445.AM2011-2954
Abstract 2957: Mutations of Cyclin D1 / beta-catenin are coexistent with mutations in Ras-PI3K pathway genes in endometrial cancer
Authors: Ikeda Yuji , Oda Katsutoshi , Nakagawa Shunsuke , Shoji Keiko , Kashiyama Tomoko , Ishikawa Shumpei , Yamamoto Shogo , Tanikawa Michihiro , Hiraike Osamu , Aburatani Hiroyuki , Yano Tetsu , Taketani Yuji 
Published: June 2012

Abstract
Introduction: Mutant beta-catenin is translocated to nucleus, and induces Cyclin D1 expression. Cyclin D1 cooperates with CDK4/6 to accelerate cell cycle from G1 to S phase. In addition to canonical Wnt signaling pathway, beta-catenin is regulated by GSK-3beta, which is phosphorylated and downregulated by Akt. Endometrial carcinoma is the only tumor type, in which CyclinD1 mutations have been reported. Mutations of beta-catenin and Ras-PI3K pathway genes (such as K-Ras, PTEN and PIK3CA) are also well-known in endometrial cancer. In this study, we analyzed alterations of Cyclin D1 and beta-catenin, and addressed the relationship between these alterations and the Ras-PI3K activating mutations in endometrial cancer.
Materials and methods: We extracted DNA from 91 primary endometrial carcinomas (under informed consent) and 13 endometrial carcinoma cell lines. Mutations of CCND1 (Cyclin D1), CTNNB1 (beta-catenin), K-Ras, PTEN and PIK3CA were analyzed by PCR-direct sequencing. In 24 cliniclal samples, Single Nucleotide Polymorphism (SNP) typing arrays (50K) were performed to evaluate copy number alterations in 11q13.3 for CCND1, 3p22.1 for CTNNB1, 12p12.1 for K-Ras, 10q23.3 for PTEN and 3q26.3 for PIK3CA.
Result: Alterations of Cyclin D1 were detected in three clinical samples; mutations in two (2%) and amplification in one (4%) samples. Mutations of beta-catenin were detected in nine clinical samples (10%) and four cell lines (31%). No overlapping alterations were observed in Cyclin D1 and beta catenin. All the tumors with alterations in Cyclin D1 or beta-catenin coexist with mutations in the Ras-PI3K pathway genes (K-Ras, PTEN and PIK3CA). All the three patients with Cyclin D1 alterations were poor prognostic, whereas all the nine patients with beta-catenin mutations were alive without recurrence.
Conclusion: Our data suggest that tumors with mutations in beta-catenin or Cyclin D1 could more efficiently accelerate cell cycle by cooperating with the coexistent alterations in the Ras-PI3K pathway genes. Furthermore, Cyclin D1 mutation might be associated with tumor aggressiveness and poor prognosis in endometrial cancer.
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 2957. doi:10.1158/1538-7445.AM2011-2957
Abstract 2959: The Syk tyrosine kinase negatively affects cell cycle progression through phosphorylation of the Cdk1 kinase in response to DNA damage
Authors: Saen Michael , Morel Anne , Larive Romain , Urbach Serge , Jouin Patrick , Morris May C. , Dulic Vjekoslav , Mangeat Paul , Coopman Peter J. 
Published: June 2012

Abstract
The non-receptor spleen tyrosine kinase Syk has mainly been studied in hematopoietic cells in which it plays a key role in the immune-response signalling. We previously demonstrated that Syk is also present in mammary epithelial cells and that its expression is lost during malignant progression of breast cancer cell lines. Clinical studies confirmed loss of Syk expression, not only in breast tumors but also in other carcinomas and melanoma. Xenotransplantation animal experiments evidenced that Syk acts as a tumor and metastasis suppressor in breast cancer and melanoma. The mechanisms by which Syk exerts its anti-oncogenic activity remain, however, unrevealed. We previously demonstrated that Syk localizes to the centrosomes and negatively affects cell division. The centrosomal Syk substrates and possible effectors of its anti-oncogenic activity remain, nevertheless, unknown. In this study, we demonstrate that Syk may negatively affect cell cycle progression through the phosphorylation of the Cdk1 kinase, a key protein involved in the control of mitosis.
Using immunofluorescence, we observed that endogenous Syk and Cdk1 colocalize at the centrosomes and that transient DsRed-Syk transfection induces pY15-Cdk1-positive epitopes at the centrosomes. In vitro kinase assays demonstrate that Syk can phosphorylate Cdk1 in the presence of different cyclins. Mass spectrometry allowed identification of four different Cdk1 tyrosine residues phosphorylated by Syk, amongst which the Y15 is known to negatively affect mitotic entry when phosphorylated by the Wee1 kinase. Transient overexpression of DsRed-Syk or GFP-Cdk1 carrying phospho-mimicking mutations resulted in a cell cycle block as observed by FACS analysis and led to a senescence-like growth arrest. Finally, we demonstrate that DNA damage-inducing agents induce Syk activation and Cdk1 tyrosine phosphorylation in a Syk-dependent manner, as evidenced by the use of a Syk-targeting shRNA.
In conclusion, our results reveal that Syk overexpression or Syk activation by genotoxic agents induce a cell cycle arrest through the phosphorylation of Cdk1. These novel aspects of Syk function will contribute to a better understanding of its onco-suppressive activity and, more generally, of the DNA damage-induced signalling.
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 2959. doi:10.1158/1538-7445.AM2011-2959
Abstract 2961: Spatiotemporal regulation of the SCF ubiquitin ligase component, Fbxo7
Authors: Nelson David E. , Laman Heike 
Published: June 2012

Abstract
Fbxo7 is a member of the F-box family of proteins which direct the E3 ubiquitin ligase activity of the SCF holoenzyme. Apart from the SCF, Fbxo7 is also able to function as an assembly scaffold for Cyclin D/Cdk6 complexes, promoting cellular transformation. The expression of Fbxo7 in immortalised embryonic fibroblasts rendered them invasive and capable of anchorage independent growth and tumour formation in nude mice. Moreover, transformation was dependent on the presence of Cdk6. In recent experiments we showed that the over-expression of Fbxo7 in haematopoietic stem cells cooperated with p53 mutation to promote T cell lymphoma in adoptive transfer experiments conducted in mice, demonstrating it is a sensitive and causal agent in oncogenesis. In human cancers, Fbxo7 was found to be highly expressed in various tumours, including haematopoietic malignancies, as well as lung and colon carcinomas. Interestingly, in a number of these tumour samples, the subcellular distribution of Fbxo7 was altered, changed from predominantly cytoplasmic to nuclear, suggesting that the localization of Fbxo7 is critical to its function.
We found that in proliferating cells, the localization of Fbxo7 was altered during the cell cycle phase: cytoplasmic during G1, and accumulating in the nucleus during S-G2. We have identified a functional NES motif embedded within the F-box domain of Fbxo7, the region which regulates its interaction with the SCF holoenzyme through binding to Skp1. Loss of the F-box domain it its entirety or targeted mutation of the NES renders the protein constitutively nuclear. We find also that binding of Fbxo7 to Skp1 prevents its interaction with Crm1, a component of the nuclear export machinery suggesting that association with the other SCF components directly promotes the nuclear accumulation of the protein. These findings suggest that during the latter part of the cell cycle SCF(Fbxo7) ubiquitin ligase activity is directed against a nuclear protein. A recent proteomics screen has now revealed new substrates for Fbxo7 within the nucleus which may help to decipher how the deregulation of the spatiotemporal regulation of Fbxo7 contributes to its role in cancer.
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 2961. doi:10.1158/1538-7445.AM2011-2961
Abstract 2962: A rapid alternative method for cell cycle analysis using the Cellometer Vision
Authors: Chan Leo L. , Zhong Xuemei , Qiu Jean , Li Peter , Lin Bo 
Published: June 2012

Abstract
Traditional cell cycle analysis instrumentation involves the use of fluorescence microscopy, laser scanning cytometry, and flow cytometry. In this work, we demonstrate a rapid alternative device, the Cellometer Vision, which utilizes an imaging cytometry method for analyzing cell cycle measurement. This method employs both bright-field and fluorescence imaging of a disposable cell counting chamber to quickly provide concentration and percentages of cell subpopulations. Signal measurement and data analysis could be performed less than five min. Cell cycle assay was demonstrated by detection of changes in phase percentage within a cell population when Jurkat cells were induced with three different drugs, nocodazole, etoposide, and aphidicolin that arrest cell cycle at G2/M, S, and G0/G1 phase, respectively. Jurkat cells were fixed with 75% ethanol and stained with propidium iodide. Individual cells were identified by the software and the fluorescence intensity was measured from within the cell. The imaging cytometry method was able to detect and analyze fluorescence from the Jurkat cells, which generated cell cycle data plot for each drug at three different concentrations. The cell cycle analysis results were highly consistent with the results obtained from FACScalibur flow cytometer. This imaging cytometry method provides a rapid and cost-effective tool for cell concentration measurements, as well as cell cycle analysis, which may benefit smaller research laboratories, where flow cytometer is not readily available.
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 2962. doi:10.1158/1538-7445.AM2011-2962
Abstract 2968: The functional relationship between CHFR and PARP-1 controls the antephase checkpoint and tumor development
Authors: Kashima Lisa , Mita Hiroaki , Idogawa Masashi , Toyota Minoru , Sasaki Yasushi , Tokino Takashi 
Published: June 2012

Abstract
The mitotic checkpoint gene CHFR is silenced by promoter hypermethylation or mutated in various human cancers, suggesting that CHFR is an important tumor suppressor. Recent studies have reported that CHFR functions as an E3 ubiquitin ligase of Aurora A and HDAC1, resulting in the degradation of those proteins. To better understand how CHFR suppresses cell cycle progression and tumorigenesis, we sought to identify CHFR-interacting proteins using affinity purification combined with mass spectrometry. Poly (ADP-ribose) polymerase-1 (PARP-1), which catalyzes polyADP-ribosylation, was newly identified as a CHFR interacting protein. CHFR promoted polyubiquitination of PARP-1. Conversely, PARP-1 poly(ADP-ribosyl)ated CHFR. In addition, we mapped the region of both CHFR and PARP-1 required for the interaction. Because CHFR delays entry into metaphase in response to mitotic stress, we investigated whether PARP-1 is involved in the mitotic checkpoint. In the presence of PARP-1, CHFR arrested the cell cycle. On the other hand, in the absence of PARP-1, CHFR had no effect on the cell cycle arrest. Additionally, we found the knockdown of PARP-1 resulted in cell cycle arrest itself. As overexpression of PARP-1 has been reported in several human tumors, our findings suggest the functional relationships between CHFR and PARP-1 could play an important role in regulation of cell cycle and tumor suppression.
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 2968. doi:10.1158/1538-7445.AM2011-2968
Abstract 2971: The modulation checkpoint signaling by natural products during the DNA damage response
Authors: Nishida Hiroshi , Kawakami Kayoko , Tatewaki Naoto , Hirayama Masao , Ikekawa Nobuo , Konishi Tetsuya 
Published: June 2012

Abstract
ATM (ataxia telangiectasia mutated) and ATR (AT and Rad3 related) protein kinases play a crucial role in cellular DNA damage responses. The inhibition of these kinases and/or related signaling molecules lead to an abolishment of one such signal pathways termed as checkpoints. It is expected that the discovery of checkpoint modulator such as natural products will be an effective assistance of anti-cancer therapy with lower side effect. In the present study, we demonstrated the inhibitory effect of Squalene (SQ), flavonoids derived from Persimmon leaves (PL) and Schisandrin-B (SchB) on ATM/ATR-dependent checkpoint signaling pathway. The cell viability was decreased by SQ, PL or SchB treated A549 adenocarcinoma after gamma-irradiation (IR) or UV exposure. In each SQ, PL and SchB treated cells, G2/M checkpoint activity was abolished in DNA damaged cells. In vitro kinase assay revealed that PL and SchB inhibits ATM and ATR, respectively. SQ, on the other hand, showed no effect on both kinases. Interestingly, SQ increased Wip1 protein expression in unperturbed cells, and suppressed ATM activation in IR treated cells. Consistent with potential inhibition of ATM by SQ or PL, IR-induced phosphorylations of ATM effectors such as p53 (S15) and Chk1 (S317) were remarkably inhibited by the treatment of SQ or PL. SchB inhibited the specific phosphorylation of these effectors by ATR. Moreover, Xenograft and allograft studies with natural products were demonstrated that the tumor growth of both cancer cells in vivo were obviously inhibited by SQ, PL or SchB treatment. These results suggest that some natural products such as SQ, PL and SchB might be applicable to the sensitization of anti-cancer therapies such as radio- /chemotherapy.
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 2971. doi:10.1158/1538-7445.AM2011-2971