bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5024: Sorafenib in combination with modifiers of epigenetic mechanism induce synergistic cytotoxicity in human liver cancer cell lines
Authors: Gaur Shikha , Chen Linling , Yen Yun 
Published: February 2011

Abstract
Background: Hepatocellular carcinoma (HCC) is the third most important cause of cancer death worldwide. Sorafenib, a multikinase inhibitor improved outcomes in patients with hepatocellular carcinoma (HCC) by inhibiting angiogenesis. Epigenetic research suggests that many cancers may not be caused by mutations in genes but by chemical modifications that change how the genes function. DNA methylation and histone deacetylation are two of the more widely studied epigenetic mechanisms. Inhibitors of DNA methylation (Vidaza) and histone deacetylation (SAHA) have shown inhibited cell growth and induced apoptosis in liver cancer cells. We investigated the cytotoxicity of combination of Sorafenib with SAHA or Vidaza in two liver cancer cell lines HepG2 and Hep3B. METHODS: HepG2 and Hep3B cells in log phase growth were treated simultaneously with sorafenib (0.5-10 µM) and/or vidaza (1.25-10 µM) or SAHA (1.25-10 µM) for 72 hours. Following drug treatment, MTS assay was used as the endpoint for cell proliferation and the IC50 values and combination indices (CI) were derived using Calcusyn software (Biosoft, Cambridge, UK). Each combination was repeated at least three times.
RESULTS: The mean single agent IC50's for Sorafenib, Vidaza and SAHA were 6.83±0.44 µM, 10.33±2.91µM, and 11.5±4.25 µM, respectively in HepG2 cells and 6.25±0.20 µM, 11.50±0.41 µM, and 4.25±0.20 µM, respectively in Hep3B cells. The combination indices were:CombinationsHepG2Hep3BSorafenib and Vidaza0.72+0.130.73+0.12Sorafenib and SAHA0.77+0.130.68+0.05
CONCLUSIONS: The CI's for both combinations demonstrated synergistic effects in each of the cell lines. The molecular mechanism behind the synergistic effect of sorafenib in combination with vidaza or SAHA in liver cancer in underway.
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 5024.
Abstract 503: Curcumin protects UV-induced skin damage in SKH-1 hairless mouse
Authors: Cherng Jaw-Ming , Yu Alice Yu-whay , Lin Jung-Chung 
Published: February 2011

Abstract
Exposure to ultraviolet (UV) light is the major etiologic factor leading to the development of cutaneous squamous and basal cell carcinoma and is also a risk factor for melanomas. UV elicits inflammation, epidermal hyperplasia and changes in the expression of numerous genes associated with proliferation and differentiation. Curcumin has been shown to exert an anti-inflammatory activity, interfere with multiple cell signaling pathways, and possess potential preventive effect against various cancers. The purpose of this study was to determine whether curcumin can protect UV-induced skin damage in hairless SKH-1 mice. Oral or topical application of curcumin prior to, or immediately after, UV irradiation resulted in a very strong protective effect against UV-induced thymine dimer expression in epidermis, accounting for 69-74% inhibition (p &lt; 0.00). Curcumin treatment also resulted in upregulation of p53 and p21/Cip1 protein levels by 33-41% (p &lt; 0.005) and 46-50% (p &lt; 0.005), respectively. Oral or topical application of curcumin prior to, or immediately after UV irradiation strongly decreased the expression of proliferative cell nuclear antigen by 47- 56% (p &lt; 0.005). In addition, curcumin treatment significantly suppressed UV-induced apoptosis as measured by TUNEL assays (p &lt; 0.005). Furthermore, curcumin treatment also significantly inhibited NF-κB, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and nitric oxide (NO) levels. Our results suggest that curcumin possesses strong protective effect against UV-caused damage in epidermis. Taken together, these results provide a focus for the rational development of curcumin as a novel chemopreventive agent against UV-induced human skin 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 503.
Abstract 5034: Both host and tumor cells group VIA phospholipase A2 are involved in ovarian cancer development, and lysophosphatidic acid restores the lost activities
Authors: Li Hui , Zhao Zhenwen , Wei Gang , Wang Dongmei , Zhang Hong , Turk John , Xu Yan 
Published: February 2011

Abstract
Host-tumor cell interactions are recognized to be critical in tumor development. We have shown that group VIA phospholipase A2 (calcium-independent phospholipase A2beta, iPLA2β) is important in regulating extracellular lysophosphatidic acid (LPA) levels around human epithelial ovarian cancer (EOC) cells. To explore the role of iPLA2β in host-tumor cell interactions, we have used immunocompetent iPLA2β knockout (KO) mice and the mouse EOC cell line ID8. Tumorigenesis and ascites formation were reduced in iPLA2β-KO mice compared to wild type (WT) mice and were reduced further when ID8 cell iPLA2β levels were lowered with shRNA. LPA and lysophosphatidylcholine (LPC) levels in the tumor microenvironment were reduced in KO mice. LPA, but not LPC, restored ID8 cell migration, invasion, and colony formation with cells in which iPLA2β expression had been suppressed in vitro. LPA, but not LPC, also enhanced in vivo ascites formation and tumorigenesis in iPLA2β-KO mice. Autotaxin (ATX) activity in the tumor microenvironment correlated with tumor loading and was reduced in KO mice and enhanced by LPA in vivo. This is the first demonstration of a role for host cell iPLA2β in cancer, and these findings suggest that iPLA2β is a potential target for developing novel antineoplastic therapeutic strategies.
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 5034.
Abstract 5036: NF-κB pathway inhibition delays the onset of MYC-induced liver cancer
Authors: Bellovin David I. , Adam Stacey J. , Yang Qiwei , Felsher Dean W. 
Published: February 2011

Abstract
Liver cancer is one of the most lethal forms of cancer worldwide. Hence, it is critical to identify pathways that may be essential for the genesis of liver cancer and can thus be considered as targets for therapeutic intervention. Previously, our laboratory developed a conditional transgenic murine model of MYC-induced liver cancer that is dependent upon the expression of this oncogene and regresses following its inactivation. Here, we present evidence of an important role for the nuclear factor-kappa B (NF-κB) pathway in MYC-induced hepatocarcinogenesis. In order to examine whether NF-κB activation is necessary for MYC-induced liver cancer, we established a transgenic system in which MYC can be activated in hepatocytes concomitantly with a mutant form of IκB, thereby inhibiting the NF-κB pathway. Our approach has revealed that suppression of NF-κB activation can significantly inhibit MYC-induced hepatocellular carcinoma (HCC) in adult hosts. Indeed, animals with hepatocyte-inhibited NF-κB remain tumor free up to 8 months after oncogene activation compared to mortality in 100% within 6 months in animals expressing MYC alone. Moreover, inhibition of NF-κB reduces disease penetrance from 100% to 75%. In hosts that do develop liver tumors, there is evidence for activation of the NF-κB pathway, suggesting a necessity for NF-κB activation in MYC-induced HCC. Importantly, suppression of NF-κB activation in neonatal hosts is not only able to similarly suppress MYC-induced tumor formation, but animals that develop liver cancer in this context demonstrate a strikingly altered tumor phenotype. In addition, MYC inactivation results in a concomitant decrease in expression of NF-κB target genes, suggesting a direct role of MYC in the activation of NF-κB in hepatocytes. The inhibition of NF-κB did not result in increased apoptosis upon MYC activation. Rather, NF-κB activation may be important for MYC to evade oncogene-induced senescence, thereby facilitating tumorigenesis. Our data suggests that the inhibition of the NF-κB pathway may be sufficient to abrogate MYC's ability to induce tumorigenesis in the liver and thereby establish NF-κB activation as an attractive therapeutic target for liver 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 5036.
Abstract 5044: Dual GSK-3β/CDK inhibitors induce multiple myeloma cell death and eliminate putative cancer stem cell populations
Authors: Dolloff Nathan G. , Hart Lori S. , Mayes Patrick A. , El-Deiry Wafik S. 
Published: February 2011

Abstract
Multiple myeloma (MM) is a plasma cell malignancy that recurs in 100% of patients despite high treatment response rates. The incurable nature of the disease and the low proliferative capacity of terminally differentiated MM plasma cells supports the existence of a cancer stem cell (CSC) component - a cell population with self-renewal and drug resistance properties capable of repopulating the disease after seemingly effective treatment and periods of undetectable disease. It is imperative to develop new therapies that target both terminally differentiated MM plasma cells and MM CSCs to extend disease-free survival and control the disease. We tested the ability of c-Myc-inducing compounds, such as GSK-3β and dual GSK-3β/CDK inhibitors, to enhance the activity of bortezomib against advanced MM cell lines (RPM-I8226 and NCI-H929). We have shown that this class of inhibitors has anti-tumor effects and sensitizes numerous solid malignancies to apoptosis-inducing agents (Mayes P.A., Dolloff N.G. et al., in revision). Moreover, c-Myc expression increases protein translation, and in doing so, enhances the cytotoxicity of proteasome inhibitors such as bortezomib (Nawrocki et al., 2008). We found that GSK-3β inhibitors (lithium choloride and sc-24020) failed to induce apoptosis or reduce viability of MM cell lines or to enhance the activity of bortezomib. By contrast, the dual GSK-3β/CDK inhibitors, alsterpaullone and the nucleoside analogue SLM3 (Mayes P.A., Dolloff, N.G. et al., in revision), were highly toxic to MM cells both alone and in combination with bortezomib. In addition to inducing massive apoptosis and reducing MM cell viability, alsterpaullone and SLM3 eliminated the presence of dye-effluxing side-populations, that have been shown to exhibit CSC behavior in vitro and in animal models of MM. By comparison, bortezomib, adriamycin and melphalan increased the percentage of MM side-population cells, suggesting that MM CSC cells are more resistant to these agents compared to their non-CSC counterparts. Interestingly, alsterpaullone and SLM3 eliminate a distinctly large sub-population of MM cells that are enriched in side-population cells, providing a further characterization of the MM CSC phenotype. We propose that using GSK-3β/CDK inhibitors may be effective therapies, as they target tumorigenic CSC populations, which are responsible for disease relapse. We are currently testing this hypothesis in mouse models of MM.
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 5044.
Abstract 5048: TAp73a enhances the cellular chemosensitivity to cisplatin in ovarian cancer cells
Authors: Zhang Pingde , Liu Stephanie S. , Ngan Hextan YS 
Published: February 2011

Abstract
Ovarian cancer is the most lethal gynecological malignancy. Most ovarian cancer patients relapse and subsequently die due to the development of resistance to chemotherapy. Strategies for overcoming resistance to chemotherapy and improving prognosis of ovarian cancer patients are very critical. P73, one member of the tumor suppressor p53 family, shares highly structural and functional similarity to p53. Established evidence showed that p73 mediated cellular sensitivity to chemotherapeutic agents in some human tumor cells. However, the role of p73 in the regulation of cellular response to DNA damaging agents in ovarian cancer is still poorly understood, and the function of the transcriptionally active isoform TAp73 as a tumor suppressor is still controversial. The aim of the present study was to examine the effect of TAp73a on cellular response to commonly used chemotherapeutic agent cisplatin in ovarian cancer cells. We established TAp73a overexpressed stable clones in two ovarian cancer cell lines: OVCA433 (wild-type p53) and SKOV3 (null p53). We found that TAp73a enhanced chemosensitivity of ovarian cancer cells to cisplatin by inhibiting cell growth and inducing cell cycle arrest and apoptosis in wild-type p53 OVCA433 cells. Additionally, TAp73a up-regulated the p53 expression and its downstream genes: PUMA, NOXA, p53AIP1, and down-regulated the phosphorylation of Akt as assessed by western blotting. The accumulation of p53 protein induced by TAp73a was found at the post-transcriptional level. Co-immunoprecipitation assay demonstrated that TAp73a directly bound to p53 protein, suggesting that such interaction might block the degradation of p53 protein in OVCA433 cells. In p53-null SKOV3 cells, the increase of chemosensitivity induced by TAp73a was also observed, indicating that TAp73a also functioned independent of p53 by up-regulating the cell cycle inhibitor p21 expression. In conclusion, these results suggested that TAp73a might play an important role in the enhancement of cellular sensitivity to chemotherapeutic drug cisplatin in ovarian cancer cells through p53 dependent and independent pathways.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 5048.
Abstract 5051: Overexpression of talin 1 (TLN1) in invasive oral squamous cell carcinoma (OSCC)
Authors: Sheu Jim J. , Lai Ming-Tsung , Tseng Hsien-Chang , Lin Ying-Ju , Wan Lei , Hua Chun-Hung , Tsai Ming-Hsui , Chiu I-Wen , Chang Nai-Wen , Lin Chin-Fen , Chen Chih-Mei , Lee Min-Min , Tsai Fuu-Jen 
Published: February 2011

Abstract
Oral squamous cell carcinoma (OSCC) is a highly invasive disease displaying frequent tumor recurrence and lymph node metastasis. Genes involved in cytoskeleton remodeling, cell attachment, and cell mobility are suspicious candidates that promote invasiveness. A genomewide study based on Sty1 250K SNP array platform revealed the involvement of TLN1 gene in the 9p13.3 amplicon. Although large scale screening on 123 tumor tissues by dual color-fluorescence in situ hybridization (FISH) indicated low frequency (around 7.3%) of TLN1 amplification in OSCC, the overall gene expression levels were significantly higher in tumor tissues as compared to the adjacent normal oral epithelium (P &lt; 0.01). As compared to other cytoskeleton crossing linkers that can trigger integrin activation, TLN1 stood out to be the most highly expressed one in OSCC. A mouse study revealed that TLN1 overexpression could be detected in invasive tumors but not in the lesions at early stages. Immunohistochemistry (IHC) data revealed stronger TLN1 immunereactivity in OSCC than in normal tissues. More intense staining pattern was detected at the leading edge of cancer cells under going angiogenesis or lymphogenesis. Patients with TLN1 overexpression had a significantly shorter overall survival and higher recurrence rate than those without. Collectively, our study suggested an important role of TLN1 in oral cancer progression.
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 5051.
Abstract 5054: The interplay between Disabled-2 and protein kinase C epsilon in the regulation of prostate cancer cell survival
Authors: Tseng Wei-Lien , Chen Yan-Yu , Cheng Ju-Chien , Tseng Ching-Ping 
Published: February 2011

Abstract
Prostate cancer is the leading cause of cancer-related death in men in the world. Previous studies have demonstrated that Disabled-2 (DAB2) is a tumor suppressor and down-regulation of DAB2 expression is accompanied with prostate cancer progression. On the other hands, protein kinase C epsilon (PKCε) functions as an oncogene and promotes human prostate cancer cell survival upon treatment of methyseleninic acid (MSA), an anti-cancer agent that induces prostate cancer cell apoptosis. However, little is known whether there is a crosstalk between DAB2 and PKCε. In this study, we first analyzed DAB2 and PKCε protein expression in three prostate cancer cell lines DU145, PC3 and C4-2. Western blot analysis revealed that DAB2 was relatively abundant in PC3 when compared with the DU145 and C4-2 cells. In contrast, the expression of PKCε was higher in DU145 and C4-2 cells when compared with the PC3 cells. Consistent with these findings, ectopic expression of DAB2 resulted in down-regulation of PKCε. These observations implicate a reverse association of DAB2 and PKCε and suggest that DAB2 is a regulator of PKCε expression. To further explore the interplay between DAB2 and PKCε, we determined the effect of DAB2 overexpression on DU145 cell susceptibility to MSA-induced cell death. Consistent with a previous report, overexpression of PKCε increased DU145 cell survival and knockdown of PKCε by small interfering RNA augmented cell death upon treatment of MSA but not Ibupofen. Accordingly, expression of DAB2 down-regulated PKCε and increased in cell susceptibility to MSA that resulted in a 40% decrease of cell survival. These findings suggest that DAB2 modulates PKCε expression and affects prostate cancer cell susceptibility to selective anti-cancer agents. This study represents the first report to unveil the interplay between DAB2, PKCε and prostate cancer cell survival.
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 5054.
Abstract 5055: TOPK phosphorylation of Prx1 at Ser32 prevents UVB-induced apoptosis in RPMI7951 melanoma cells through regulation of its peroxidase activity and blockade of intracellular accumulation of H2O2
Authors: Zykova Tatyana , Zhu Feng , Vakorina Tatyana I. , Zhang Jishuai , Higgins LeeAnn , Urusova Dasha V. , Bode Ann M. , Dong Zigang 
Published: February 2011

Abstract
A novel serine/threonine kinase, T-LAK cell-originated protein kinase (TOPK), is only expressed in a wide range of cancer cells. We previously showed that TOPK increases colorectal cancer growth in vivo and ex vivo and that melanoma cell lines with a high abundance of TOPK protein exhibit a marked resistance to As3+-induced apoptosis. Here we continue our investigation of the functional details of TOPK. LC/MS/MS data showed that TOPK can bind with peroxiredoxin 1 (Prx1), which regulates hydrogen peroxide-mediated signal transduction. The role of Prx1 phosphorylation induced by UV in melanoma is not clear. Here, we provide evidence that TOPK phosphorylates Prx1 at Ser32 in vitro. Analysis of the CD spectra of Prx1 and a mutant Prx1 (S32A) protein shows that the secondary structure of Prx1 was significantly altered by its phosphorylation at Ser32. UVB radiation induced phosphorylation of TOPK in a time-dependent manner in RPMI7951 human melanoma cells and phosphorylated TOPK co-localized with Prx1 in the nucleus. UVB treatment increased peroxidase activity of Prx1 in vitro and ex vivo. The level of H2O2 was increased in TOPK siRNA cells and in RPMI7951 cells stably overexpressing mutant Prx1 (S32A). In addition, apoptosis was dramatically increased in TOPK siRNA cells and decreased in WT-Prx1 stable cells after UVB treatment. Our results suggested that TOPK phosphorylation of Prx1 at Ser 32 prevents UVB-induced apoptosis in RPMI7951 melanoma cells through the regulation of Prx1 peroxidase activity by blocking intracellular accumulation of H2O2.
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 5055.
Abstract 5056: Signaling pathways critical for insulin receptor substrate (IRS)-mediated disruption of MCF-10A acini formation
Authors: Chan Bonita Tak-Yee , Kuiatse Isere , Lee Adrian V. 
Published: February 2011

Abstract
Insulin receptor substrate (IRS)-1 and IRS-2 are important adaptor proteins in insulin-like growth factor-I receptor (IGF-IR) signaling. IRS-1 and IRS-2 are expressed during mammary gland development and also in human breast tumors. In order to study the role of IRS-1 and IRS-2 in breast tumorigenesis, we overexpressed both IRS proteins in immortalized, non-transformed human mammary epithelial MCF-10A cells. It has been shown that MCF-10A cells form uniform, empty-lumen acini in three dimensional (3D) culture. We previously showed that overexpression of either IRS-1 or IRS-2 in MCF-10A cells disrupted the acini in 3D culture and resulted in extensive proliferation and disrupted apical-basal polarity. In both IRS-1 and IRS-2 overexpressing MCF-10A cells, an increase in tyrosine phosphorylation and association with p85 of both IRS proteins indicated that IRS-mediated signaling was activated. siRNA knockdown of the overexpressed IRS proteins reversed the disruption of MCF-10A acini, confirming that this is indeed an IRS-related event. In order to identify the critical effectors in IRS-mediated disruption of MCF-10A polarity and growth, we used small molecule inhibitors to screen multiple kinase signaling pathways upstream and downstream of the IRS proteins. Inhibition of Rac or atypical PKC (aPKC) didn't affect MCF-10A cell acini formation, however it abolished the IRS-mediated disruption of MCF-10A acini formation. Consistent with this, knockdown of Rac and aPKC by siRNA suppressed IRS-mediated disruption in acini formation. Rac belongs to the family of GTPase that regulates cell motility. aPKC is a key component of the PAR polarity complex, and has previously been shown to be involved in IRS-signaling in adipocytes. While the signaling mechanism of Rac and aPKC in the IRSs-induced disruption of acini is still unknown, we found that another component in the PAR polarity complex Par3 may associate with IRS proteins and leads to dissociation of the polarity complex. Taken together, overexpression of IRS-1 and IRS-2 disrupts the MCF-10A acini in 3D culture in part through Rac and aPKC pathways.
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 5056.