bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2855: SRC represents a potential therapeutic target in liposarcoma
Authors: Sievers Elisabeth , Trautmann Marcel , Kindler Dagmar , Pedeutour Florence , Aman Pierre , Nishio Jun , Wardelmann Eva , Büttner Reinhard , Hartmann Wolfgang 
Published: August 2012

Abstract
Liposarcomas (LS) represent the most common malignant soft tissue tumors in adults. Therapeutic outcome of LS is mainly determined by the efficiency of surgery as a high tendency for local relapse is seen. Chemo- and radiotherapy represent further therapeutic options, however, specifically targeted therapies are currently not available. The oncoprotein SRC is a tyrosine kinase, which has been shown to be activated in a variety of human cancers. SRC activation plays an important role in cancer cell proliferation, survival, angiogenesis and motility. In this work we analyzed LS biopsies comprising the main different subgroups, i.e. myxoid (MLS), well/dedifferentiated (WDLS/DDLS) and pleomorphic (PLS) LS and corresponding cell lines regarding SRC activation and studied the biological effects of SRC inhibition. Based on data derived from phospho-kinase screens in LS cells, immunhistochemical stainings of (Tyr416)-phosphorylated (p)-SRC were performed in primary LS biopsies. LS cell lines treated with the SRC inhibitor dasatinib were analyzed for phosphorylation of SRC and its downstream signaling molecules, cell proliferation, migration and apoptosis. Furthermore, synergistic effects of simultaneous treatments with dasatinib and conventional cytotoxic drugs were investigated. Particularly WDLS/DDLS and MLS tumor cells showed a significant expression of p-SRC. In LS cell lines, inhibition of SRC with dasatinib resulted in a substantially impaired cellular growth accompanied by a decreased phosphorylation of SRC and its downstream targets. Flow cytometric analysis showed that effects of SRC inhibition were due to an increase in apoptosis (cleaved PARP(Asp 214)) and a decrease of cellular proliferation (phospho-(Ser10) Histone H3). Scratch and Boyden chamber assays indicated a diminished migratory potential of the tumor cells due to SRC inactivation. Simultaneous treatment of liposarcoma cell lines with dasatinib and chemotherapeutic drugs resulted in additive effects. Our data suggest that SRC kinase activation represents an important biological feature of LS which might be successfully addressed in targeted therapeutic approaches.
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 2855. doi:1538-7445.AM2012-2855
Abstract 2871: Inhibition of androgen receptor-mediated expression of prostate derived ets transcription factor (PDEF) induces a loss of prostate cancer cell differentiation
Authors: haller Andrew C. , Li Fengzhi 
Published: August 2012

Abstract
While inhibition of androgen signaling has shown to extend the lives of many patients, there is a growing concern in the field that androgen ablation may select for a more aggressive and lethal phenotype of prostate cancer. It has long been known that androgen receptor (AR) mediates growth and cellular differentiation. Therefore, inhibition of AR may stem cancer growth, but concurrently cause cells to de-differentiate and gain migratory and invasive properties. Prostate derived ets transcription factor (PDEF) is an AR target gene highly expressed in normal prostate tissue and has shown to be sufficient to mediate terminal epithelial cellular differentiation in the lung and colon. Previous studies in our lab have demonstrated, through retrospective IHC staining of FFPE radical prostatectomy specimens, loss of PDEF expression significantly associated with increased incidence and patients’ shorter metastatic free survival time with early stage prostate cancer. Furthermore, previous studies in the literature have detected the PDEF promoter sequence through AR ChIP-Sequencing and ChIP-on-ChIP experiments. We therefore studied the regulation of PDEF expression by AR as a potential mediator of prostate epithelial cellular differentiation. Our data indicated that anti-androgens, androgen starvation or AR shRNA was sufficient to abrogate PDEF protein and mRNA expression. Stable expression of AR shRNA or PDEF shRNA by lentiviral infection displayed a coordinate decrease in e-cadherin expression and an increase in vimentin expression, indicating a potential shift to a mesenchymal-like phenotype. This epithelial-to-mesenchymal transition was also observed in cells acutely treated with anti-androgens bicalutamide or finasteride. Together, these results demonstrate that androgen ablation therapy may directly drive cells to de-differentiate and gain migratory/invasive capabilities, and therefore should only be indicated for those patients with a very short life expectancy or co-existing morbidities.
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 2871. doi:1538-7445.AM2012-2871
Abstract 2876: Farnesyltransferase inhibitor induces p53-dependent cellular senescence in colon cancer cells
Authors: Zhu Limin , Noh Jung Hyun , Geryk-Hall Mandy , Hughes Dennis P. 
Published: August 2012

Abstract
Farnesyltransferase inhibitors (FTIs), small molecules that inhibit prenylation of multiple proteins such as Ras and Rho, have clinical promise for cancer. FTIs block malignant growth and promote cell death in a wide variety of tumor types in vitro and in vivo, but the mechanisms underlying the antitumor activity of FTIs are not completely understood. We have observed that colon cancer cell line OS187 responds to the FTI tipifarnib with a senescent phenotype, demonstrated as altered cell morphology, elevated senescence-associated β-galactosidase activity, upregulated protein and mRNA levels of senescence markers, and long-term cell cycle arrest. Our previous results also indicated that cells retaining intact p53 are more sensitive to tipifarnib than are cells with absent/inactive p53, suggesting a possible role for p53 in the senescent response to tipifarnib. To test this hypothesis, we used shRNA to reduce p53 expression in OS187 cells. Loss of p53 reversed the swollen and enlarged senescent-like cellular phenotype induced by tipifarnib. In addition, p53 knockdown cells showed less senescence-associated β-galactosidase activity than did scrambled control cells after 7-day treatment with tipifarnib. Cell viability assay suggested that p53 knockdown partially rescued the cytotoxic effects of tipifarnib at low concentrations. Western blot also demonstrated that cell cycle regulatory proteins such as p27, p21, and p15 were significantly upregulated in scrambled control cells while only a slight increase of these proteins were observed in p53 knockdown cells after tipifarnib treatment. Flow cytometry analysis showed that cells with decreased p53 level had a reduced percentage of cells in sub G1 phase when treated with a high concentration of tipifarnib, and fewer cells arresting in G2/M phase when treated with low concentration of tipifarnib compared to the scrambled control cells. This observation suggested that p53 may involve in different pathways depending on the strength of the stress signal imposed by different concentration of tipifarnib. In conclusion, these results confirm that p53 is important for inducing senescence when farnesylation is inhibited in OS187 cells. However, since p53 knockdown has very limited impact on the anti-proliferation effects of tipifarnib at high concentrations, other pathways are expected to play a role in mediating cell susceptibility to tipifarnib. Future experiments will focus on investigating the p53-independent pathways that are responsible for tipifarnib-induced senescence and apoptosis.
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 2876. doi:1538-7445.AM2012-2876
Abstract 3020: The role of NF-κB (p65) and Stat3 interplay in the regulation of radiation-induced, ICAM-1-mediated migration and invasion in glioma
Authors: Kesanakurti Divya , Maddirela Dilip , Chetty Chandramu , Rao Jasti S. 
Published: August 2012

Abstract
Aberrant activation of both NF-κB and Stat3 is associated with enhanced tumor metastasis in various cancers. In human glioma xenograft cells 4910 and 5310, irradiation (IR; 8 Gy) elevated Stat3 and p65 phosphorylation and persistent nuclear translocation in correlation with massive increases in cellular and soluble ICAM-1 levels. Co-immunoprecipitation experiments confirmed enhanced nuclear phospho-p65/phospho-Stat3 and acetyl-p65/phospho-Stat3 interactions along with enhanced invasiveness and migration in IR-treated cells. Promoter analysis indicated presence of adjacent NF-κB- and Stat3-consensus binding elements in the proximal promoter and the proximal intron-1 of the ICAM-1 promoter, whereas overlapping NF-κB/Stat3 binding motifs were identified in the distal intron-1 region. ChIP binding and promoter/luciferase reporter assays showed that IR induced prominent binding of both Stat3 and NF-κB to the proximal intron-1 region followed by the distal intron-1 and the proximal promoter regions on the ICAM-1 gene. Individual treatments with Stat3.si or JSH-23 blocked the occupancy of both Stat3 and p65 onto the ICAM-1 promoter and prevented subsequent ICAM-1-mediated migration and invasion. In addition, constitutive activation of Stat3 and NF-κB by Stat3C or TNF-α significantly elevated IR-induced migration and invasion. In vivo orthotropic experiments in nude mice showed that the Stat3.si treatment reduced tumor growth and IR-induced phopsho-Stat3/phospho-p65 and ICAM-1 expression when compared to pSV-treated controls. These results suggest that both p65 and Stat3 bind to the intronic region of ICAM-1 promoter to induce its optimal transcription in IR-treated cells and abrogation of IR-induced p65/Stat3 binding inhibits ICAM-1-mediated enhancement of malignancy in post-irradiated tumor cells. As such, the results of this study clearly have potential future therapeutic significance in glioma 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 3020. doi:1538-7445.AM2012-3020
Abstract 3026: Increase in proliferation and migration of breast cancer cells via PKC activation-induced down-regulation of BKca channel
Authors: Park Eun Sil , Mun Yun-Ja , Kang Kee Ryeon , Han Jaehee , Kang Dawon 
Published: August 2012

Abstract
Purpose: K+ channels are involved in tumorigenesis through the regulation of cell proliferation, apoptosis, migration, and invasion. However, the involvement of the large conductance Ca2+-activated K+ (BKCa) channels in the cancerous phenomenon is controversial. This study was performed to investigate whether and how BKCa channels are related to the cellular processes for tumorigenesis. Methods: Cell proliferation and migration assays were performed in non-invasive (MCF-7) and invasive (MDA-MB-231) breast cancer cells in the absence or presence of BKCa channel modulators or PKC modulators. Patch-clamp technique and reverse-transcriptase (RT)-polymerase chain reaction (PCR) were performed to study the expression of the BKCa channel in breast cancer cells. The relationship between BKCa channels and cell proliferation/migration was analyzed using gene overexpression and knock-down techniques. Results: Patch-clamp technique and RT-PCR data showed that BKCa channels were expressed in both MCF-7 and MDA-MB-231 cells. Inhibitors of BKCa channels increased cell proliferation and migration, whereas BKCa channel activators suppressed them. Overexpression of BKCa in breast cancer cells reduced proliferation and migration, whereas silencing of BKCa enhanced the proliferation and migration. BKCa inhibitors (paxilline, ChTx, and IbTx) induced PKC activation, and the PKC activation down-regulated the BKCa channel expression and activity. In addition, the treatment of PMA (a PKC activator) decreased BKCa channel expression, whereas combination of PKC inhibitors maintained the BKCa channel expression levels without reduction. Conclusion: These results show that a decrease in BKCa expression levels, which could be modulated by PKC activation, increases cell proliferation and migration in breast cancer cells and suggest that modulation of BKCa expression may regulate tumorigenesis of breast cancer cells. Key words: Breast cancer; Cell migration; K+ channels; Proliferation
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 3026. doi:1538-7445.AM2012-3026
Abstract 3030: Hypoxia induces BACH1 expression regulating colon cancer metastasis
Authors: Lee Jin Young , Jo Yeong Nang , Kim Jin-Ah , Lee Chang Woo , Lee Ok-Jun , Han Sang-Bae , Park Song-Kyu , Kang Jong Soon , Yun Jieun 
Published: August 2012

Abstract
BACH1 (BTB and CNC homology 1) is a basic region-leucine zipper (bZip) transcription factor that binds to MAREs (Maf recognition elements) and acts as a repressor of genes that regulate the oxidative stress response. It has been reported that BACH1 is a novel let-7 target and regulates breast cancer metastasis. Here we show that hypoxia induces BACH1 expression by regulating BACH1 promoter activity. In a mouse xenograft model, BACH1 depletion reduces the primary tumor growth of HCT-116 colorectal cancer cells. In addition, knockdown of BACH1 significantly decreases the invasive efficiency of colorectal cancer cells. Finally, we confirm that BACH1 expression is high in the patient samples of colorectal cancer and metastasis, unlike normal colon tissues. These results suggest BACH1 as a novel target for cancer therapeutic strategy.
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 3030. doi:1538-7445.AM2012-3030
Abstract 3033: Identification of the MUC16/CA125 interaction network: Results of a high-throughput yeast two-hybrid screening
Authors: Polterauer Stephan , Thapi Dharmarao , Schultz Nikolaus , Ouerfelli Ouathek , Chen Nancy , Rosales Nestor , Yan Xiu , Spriggs David R. 
Published: August 2012

Abstract
Background: MUC16 is a well-known serum marker for the diagnosis of ovarian cancer. MUC16 is involved in oncogenic transformation and is associated with migration, invasion, and tumor growth. Due to the large size of this mucin, the interacting partners involved in signaling and transformation have not been investigated. Materials and Methods: We performed a high-throughput yeast two-hybrid screening to investigate putative protein interactions with MUC16. A construct of the MUC16 carboxyterminus, lacking the transmembrane domain (≥mC89), was cloned into the activation domain of the yeast vector pGBKT7. Three different ovarian cancer cDNA prey libraries were tested against the bait μmC89. Of all blue yeast colonies cDNA prey-inserts were analysed with PCR and plasmids were recovered from yeast cultures. Basic Local Alignment Search Tool was used to identify corresponding genes in the GenBank Database. Gene expression- and correlation analyses of human ovarian cancer data of The Cancer Genome Atlas (TCGA) were performed. Immunoprecipitation analyses and magnetic immonoassays were performed to confirm potential interaction partners in human ovarian cancer cell lines. Results: Screening of approximately 30,000,000 colony-forming units identified 238 yeast colonies that maintained promoter activation when cultivated in selective media. PCR and sequencing of cDNA inserts of cultivated yeast colonies nominated 84 candidates as putative binding partners for MUC16. Analysis of TCGA data did not identify direct linkage between mRNA expression of MUC16 and the nominated partners in human ovarian cancers. Based on this analysis and on their biological function, six partners were chosen for further confirmatory analyses: AMHR2, eEF1α, EGF, GAL1, PPP2CB, and SEPT2. Results of the confirmation analyses are pending. Our findings suggest a role of these proteins in regulating MUC16 signaling and transformation mechanisms. Conclusions: We nominate six novel potential partners for interaction with the MUC16 carboxyterminus (≥mC89). These proteins might be involved in ovarian cancer signaling and transformation and might be useful novel targets for vaccines, antibodies and drug inhibitors for the treatment of ovarian 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 3033. doi:1538-7445.AM2012-3033
Abstract 3040: Terbinafine inhibits oral squamous cell carcinoma growth through anti-cancer cell proliferation and anti-angiogenesis
Authors: Chien Ming-Hsien , Yang Shun Fa , Lee Wen Sen 
Published: August 2012

Abstract
ABSTRACT Terbinafine (TB), an oral antifungal agent used in the treatment of superficial mycosis, has been reported to exert an anti-tumor effect in various cancer cells. However, the effect of TB on oral cancer has not been evaluated. Herein we demonstrated that TB (0-60 μM) concentration-dependently decreased cell number in cultured human oral squamous cell carcinoma (OSCC), KB cells. The anti-proliferation effect of TB was also observed in two other OSCC cell lines, SAS and SCC 15. TB (60 μM) was not cytotoxic and its inhibition on KB cell growth was reversible. [3H]thymidine incorporation and flow cytometric analyses revealed that TB inhibited DNA synthesis and induced the G0/G1 cell cycle arrest. The TB-induced cell cycle arrest occurred when the cyclin-dependent kinase 2 (CDK2) activity was inhibited just as the protein levels of p21cip1 and p27kip1 were increased. The TB-induced G0/G1 cell cycle arrest was completely blocked when the expressions of p21cip1 and p27kip1 were knocked-down together. Taken together, these results suggest that the p21cip1- and p27kip1-associated signaling pathways might be involved in the TB-induced anti-proliferation in KB cells. In vivo, TB (50 mg/kg, i.p.) significantly inhibited the KB tumor size. In these TB-treated tumors, increases in the levels of p21cip1 and p27kip1 protein and decreases in the number of proliferating cell nuclear antigen (PCNA)-positive cells and the microvessel density (MVD) were observed. These findings demonstrate for the first time that TB might have potential to serve as a therapeutic tool in the treatment of oral cancer. 1
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 3040. doi:1538-7445.AM2012-3040
Abstract 3047: MK1775, a selective Wee1 inhibitor shows antitumor activity against sarcoma cells
Authors: Kreahling Jenny M. , Foroutan Parastou , Gemmer Jennifer Y. , Martinez Gary , Reed Damon , Letson Douglas , Bui Marilyn , Gillies Rober J. , Altiok Soner 
Published: August 2012

Abstract
Sarcomas are rare and heterogeneous mesenchymal tumors affecting both pediatric and adult populations with more than 70 recognized histologies. Doxorubicin and ifosfamide have been the main course of therapy for treatment of sarcomas; however, the response rate to these therapies is about 10-20% in metastatic setting. Toxicity with the drug combination is high, response rates remain low, and improvement in overall survival, especially in the metastatic disease, remains negligible. Accordingly, new agents are needed for the treatment of this heterogeneous group of diseases. Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by a selective small molecule inhibitor MK1775 has been reported to to enhance the cytotoxic effect of DNA damaging agents. However, its role in the treatment of mesenchymal tumors has not been explored. In this study we investigated the therapeutic efficacy of MK1775 in various sarcoma cell lines and patient-derived tumor explants ex vivo both alone and in combination with other chemotherapeutic drugs frequently used in the treatment of sarcomas. Our data demonstrate that MK1775 treatment as a single agent at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. Additionally, MK1775 significantly enhances the cytotoxic effect of the DNA damaging agents, gemcitabine and doxorubicin. In MK1775 treated cells CDC2 activity was enhanced and G2/M ceheckpoint was impaired as assessed by increased expression of phosphorylated histone H3, a marker of mitotic entry. The cytotoxic effect of Wee1 inhibition on sarcoma cells appears to be independent of p53 status as all sarcoma cell lines with different p53 mutation were highly sensitive to treatment. Additionally, in patient-derived bone and soft tissue sarcoma samples we showed that MK1775 in combination with gemcitabine causes significant apoptotic cell death suggesting that this treatment may represent a novel approach in the treatment of sarcomas. In patient-derived xenograft mouse models of sarcoma we are currently analyzing the therapeutic efficacy of MK1775 in vivo by utilizing magnetic resonance imaging (MRI) and diffusion MRI methods. Our results together with the high safety profile of MK1775 strongly suggest that this drug can be used as a potential therapeutic agent in the treatment of both adult as well as pediatric sarcoma patients.
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 3047. doi:1538-7445.AM2012-3047