bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2152: Paroxetine, a selective serotonin re-uptake inhibitor, induces growth inhibition and apoptosis in prostate cancer cells
Authors: Shibuya Tadamasa 
Published: June 2012

Abstract
Introduction and Objective: Recently, neuroendocrine cells is suggested to be involved in prostate cancer (PC) progression through the secretion of a variety of neuroendocrine products, such as serotonin, which have mitogenic effects on adjacent cancer cells and thus can contribute to the androgen independent proliferation of PC cells. With having experience that a patient with hormone refractory prostate cancer responded to paroxetine, a selective serotonin re-uptake inhibitor (SSRI), in serum prostate specific antigen (PSA) level, we investigated the effect of paroxetine on the growth and apoptosis induction in PC cell lines.
Methods: Paroxetine was administered to four patients with hormone refractory, metastatic PC and their serum PSA levels were determined. The effects of paroxetine on the growth and apoptosis induction in PC cell lines (PC3, DU145, 22RV1 and LNCaP) were confirmed. Cell growth inhibition was assessed in vitro by cell number count. The induction of apoptosis was examined by flow cytometry analysis and caspase activations were confirmed by western blot analysis.
Results: Serum PSA levels decreased soon after the administration of paroxetine but increased again in all four patients but one in whom it decreased from 0.485 ng/ml to undetectable level (less than 0.008 ng/ml) for over three years. In vitro study, paroxetine inhibited cell growth in a dose and time dependent manner. The 50% inhibitory concentration (IC50 values) of paroxetine in PC3, 22RV1, DU145 and LNCaP cells were 38.8, 30.1, 35.9 and 21µM, respectively. Apoptosis induction following the treatment of paroxetine was revealed in prostate cancer cells by the increase of sub-G1 population in flow cytometry analysis and a cleavage of procaspase-3 in western blot analysis.
Conclusions: A potent SSRI, paroxetine, induces growth inhibition and apoptosis in PC cells. These results suggest that SSRIs have the potential of anti-tumor effect against PC.
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 2152. doi:10.1158/1538-7445.AM2011-2152
Abstract 2154: Simultaneous analysis of cell death mechanisms and oxidative stress using live cell fluorescence microscopy
Authors: Yan Michelle , Clarke Scott T. , Mandavilli Bhaskar S. , Huang Shih-Jung , Singh Upinder , Janes Michael S. , Dolman Nicholas J. 
Published: June 2012

Abstract
Reactive oxygen species (ROS) can directly damage DNA, proteins and lipids, while increased oxidative stress has been reported to be associated with apoptotic and autophagic cell death. Importantly, increased oxidative stress and dysregulation of cell death mechanisms have been linked with cancer development. To better understand the connection between increased oxidative stress and cell death pathways, it is important to be able to monitor both of these events simultaneously in the same cell and amongst mixed populations of cells. The goal of this study was to utilize multi-parametric fluorescence microscopy to examine the temporal progression of oxidative stress relative to cell death. By using a fluorogenic caspase substrate in combination with a near infrared fluorescent probe for ROS, we observed that increased oxidative stress was followed by activation of caspase-3/7 after induction by several agonists. We examined the effect of various agonists in both primary cells as well as cancer cell lines. Loss of mitochondrial membrane potential, nuclear condensation, and cell proliferation were also measured to establish a more comprehensive assessment of the cellular response to stress in these models. By simultaneously examining multiple parameters over time, we were able to define the temporal progression of apoptosis relative to the onset of oxidative stress. Furthermore, we were able to characterize the mechanism of cell death by discriminating between cells which were apoptotic (active caspase-3/7), autophagic (LC3B-positive autophagosomes), or both. This multi-parametric approach provided detailed spatial information at the cellular level so that correlations and temporal resolution could be determined between oxidative stress and cell death mechanisms.
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 2154. doi:10.1158/1538-7445.AM2011-2154
Abstract 2156: c-Myb promotes growth, invasion and androgen-independence of prostate cancer cells
Authors: Srivastava Sanjeev K. , Bhardwaj Arun , Singh Seema , Reed Eddie , Grizzle William , Singh Ajay P. 
Published: June 2012

Abstract
Most prostate cancer (PCa) patients treated with first line androgen-deprivation therapy (ADT) initially exhibit a dramatic regression of the androgen-dependent (AD) cancer cells; however, the tumors eventually progress to an androgen-independent (AI) stage. The resulting hormone-refractory tumors are highly aggressive and resistant to conventional therapies. The causal mechanisms for such a transition remain largely unknown; however, a number of genetic and epigenetic alterations are believed to be involved in the process of AI progression of PCa. In an earlier study, c-Myb was identified among the genes that are amplified at higher frequency in hormone-refractory PCa. The c-Myb proto-oncogene is a cellular progenitor of v-Myb oncogenes, which encodes for a transcription factor and confers its oncogenic activity by regulating the expression of several target genes. In the present study, we have investigated the functional role of c-Myb in prostate cancer cells. Our data showed that c-Myb was overexpressed in AI (C4-2) PCa cells as compared to AD (LNCaP) PCa cells of the same genotypic lineage. Furthermore, we found that c-Myb was regulated by androgens in a biphasic manner and its expression correlated with the effect of androgens on prostate cancer cell growth. Short-hairpin RNA (shRNA)-mediated silencing of c-Myb in C4-2 cells reduced their growth, clonogenicity, motility and invasion, whereas its ectopic expression in LNCaP cells had opposite effects. Moreover, we observed that the overexpression of c-Myb in LNCaP and C4-2 cells was associated with their growth in androgen-depleted media, suggesting its role in androgen-independence. Immunoblot analysis demonstrated loss of mesenchymal markers N-cadherin, vimentin, Slug, Snail, and Twist, and gain of epithelial marker, E-cadherin in c-Myb-silenced C4-2 cells. In contrast, c-Myb overexpressing LNCaP cells exhibited a loss of epithelial and gain of mesenchymal markers, thus indicating a role of c-Myb in epithelial to mesenchymal transition (EMT) of PCa cells. Altogether, our studies provide first experimental evidence for a functional role of c-Myb in altered growth, androgen-independence and malignant behavior of the prostate 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 2156. doi:10.1158/1538-7445.AM2011-2156
Abstract 2159: Molecular characterization of ERG mediated CXCR4 transcriptional regulation
Authors: Singareddy Rajareddy , John Jason Saint , Chinni Sreenivasa R. 
Published: June 2012

Abstract
CXCR4 is a chemokine receptor, which has been shown to be expressed in several types of tumor cells, and mediate invasion and metastasis. CXCR4 expression is transcriptionally regulated in cancer cells and is associated with aggressive phenotypes of prostate cancer. Previously, we and others have shown that ERG transcription factor regulates CXCR4 expression in prostate cancer cells. In prostate cancer patients ERG is expressed via chromosomal alterations resulting in fusion of androgen responsive TMPRSS2 promoter with the coding sequence of ERG transcription factor and systemic androgens regulate ERG expression. We further show that in TMPRSS2-ERG fusion positive prostate cancer cells androgens regulate CXCR4 expression via activating ERG transcription factor expression. The CXCR4 promoter contains several putative ERG/Ets transcription factor binding sites. We hypothesize that ERG binds to selective ERG/Ets binding sites in the CXCR4 promoter and activates CXCR4 expression. Using electrophoretic mobility shift assay experiments with each of the individual ERG/Ets binding sites with VCaP cell nuclear extracts and in vitro translated ERG protein, sequential ERG/Ets binding site deletions in CXCR4 promoter reporters, chromatin immunoprecipitation experiments with anti-ERG antibodies in TMPRSS2-ERG positive VCaP cells, and chemoinvasion studies with VCaP cells we show that: (a) ERG expressed in VCaP cells selectively interacts with specific ERG/Ets bindings sites in the CXCR4 promoter; (b) several Ets factor family members are expressed in VCaP cells; (c) in vitro translated ERG binding with ERG/Ets elements in CXCR4 promoter further confirms that selective ERG/Ets sites in CXCR4 promoter are active in binding with ERG; (d) ERG binds with CXCR4 gene promoter in VCaP cells; (e) androgens regulate CXCR4 expression in TMPRSS2-ERG fusion positive cells; and (f) androgen induced CXCR4 is active in chemoinvasion of prostate cancer cells. These data suggest that androgens regulate CXCR4 expression via ERG transcription factor expression and ERG factor may regulate CXCR4 expression by binding to the specific ERG/Ets responsive elements and activating CXCR4 transcription. These findings may provide a link between TMPRSS2-ERG translocations and enhanced metastasis of tumor cells via CXCR4 function in PC 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 2159. doi:10.1158/1538-7445.AM2011-2159
Abstract 2164: High fat diet-induced intraprostatic inflammation involves association between Stat-3 and NF-kappaB: Role in pathogenesis of prostate cancer
Authors: Shankar Eswar , Vykhovanets Eugene V. , Vykhovanets Olena V. , Bhaskaran Natarajan , Shukla Sanjeev , Gupta Sanjay 
Published: June 2012

Abstract
Western style high-fat diet (HFD) is a risk factor for obesity, diabetes, and cancer. In our previous studies we have demonstrated that HFD increases oxidative stress and inflammation in the prostate of NF-kappaB-luciferase transgenic reporter mice (Vykhovanets et al., Prostate 2010). However, the molecular mechanism(s) underlying HFD-induced inflammation in the prostate largely remains unknown. Signal transducer and activator of transcription (Stat-3) and nuclear factor-kappa B are the important signaling pathways that are activated during inflammation. The pro-inflammatory cytokines induced are the transcriptional targets of Stat-3 and NF-kappaB and are known to be involved in their activation. We examined the role of HFD in increasing the nuclear activation of Stat-3 and NF-kappaB and the mechanism(s) involved leading to inflammation of the prostrate. Male 16 week old C57BL/6J mice were either fed with regular diet (RD) or HFD for 4 and 8 weeks. The animals were sacrificed at the end of each time period. HFD intake caused significant increase in the plasma levels of IL-6 and IL-17, after 4 weeks of feeding that further increased after 8 weeks, compared to mice fed with RD. These cytokines have been reported to induce Stat-3. HFD intake also caused marked increase in the levels of IL-1beta and TNFalpha which are known activators of NF-kappaB. A significant increase in the levels of PKCepsilon was observed after 4 weeks of HFD feeding in these mice. Elevated levels of PDK1 and p-Akt (Ser473) were observed in the prostate tissues of HFD group. Increase in the levels of kinases corroborated with the nuclear translocation of Stat-3 and NF-kappaB/p65/RelA with significantly increased expression of Tyr705, Ser727 Stat-3 and Ser536 p65/RelA in the prostrate of HFD mice. An association between Ser727 Stat-3 and Ser 536 p65/RelA was observed in the nucleus of prostate tissue of HFD group. Furthermore, increased DNA binding of p65/RelA and Stat-3 as well as their association was observed in HFD group. Taken together, HFD increases inflammation in the prostate through activation of Stat-3 and NF-kappaB and their association may play a key role in the pathogenesis of prostate 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 2164. doi:10.1158/1538-7445.AM2011-2164
Abstract 2173: Negative transcriptional regulation of the human type III TGFβ receptor in ccRCC
Authors: Cooper Simon J. , Roemeling Christina Von , Marlow Laura , Tun Han W. , Copland John A. 
Published: June 2012

Abstract
Renal cell carcinoma (RCC) accounts for 3% of all malignancies reported each year making it the sixth leading cause of cancer death in the United States. Within this year more than 50,000 individuals will be diagnosed with RCC and around 12,000 will die from this disease. Out of these RCCs the most frequently diagnosed form is clear cell renal cell carcinoma (ccRCC) which accounts for approximately 80% of all RCCs. We have previously identified through genomic profiling that loss of the type II and III TGFβ receptors in the progression of this disease lead to loss of TGFβ responsiveness and suggests a role for dysregulated TGFβ signaling in RCC progression and metastasis. Restoration of the TGFβ receptor type III (TβRIII) leads to apoptosis in RCC cell lines (Margulis et al. 2007) suggesting that re-expression of TβRIII is an attractive method for intervention of ccRCC. Recently we identified that loss of TβRIII is an early event in ccRCC and that this loss is not through epigenetic silencing but due to the loss of transcriptional regulation. The transcription factor GATA3 was identified to be a positive regulator of TβRIII expression through its actions on the proximal promoter of TβRIII. Through deletion analysis we have now identified a region within the proximal promoter that contains a number of putative transcription factor binding sites that are capable of negatively regulating the expression of TβRIII. We have identified that one of these transcription factors is over-expressed in ccRCC patient matched renal tissue samples and that silencing of this transcription factor through lentiviral shRNA, leads to a three fold induction of endogenous TβRIII in ccRCC cell lines. Furthermore, loss of this transcription factor in ccRCC cell lines leads to decreased cell proliferation when compared to non-target infected controls. Further evaluation of these putative negatively regulating transcription factors and their actions upon the proximal promoter of TβRIII are being analyzed utilizing EMSA and ChIP assays. These investigations will identify novel molecular targets that through their dysregulation will have the potential to up-regulate TβRIII in ccRCC inducing apoptosis within these cells. Together these findings will allow for a deeper molecular understanding of the events taking place in ccRCC.
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 2173. doi:10.1158/1538-7445.AM2011-2173
Abstract 2174: Progesterone receptor, AP-1 and Stat3 cooperative transcriptional complex in breast cancer
Authors: Díaz Flaqué María C. , Béguelin Wendy , Vicario Rocio , Proietti Cecilia , Rivas Martín , Tkach Mercedes , Izzo Franco , Charreau Eduardo , Schillaci Roxana , Elizalde Patricia 
Published: June 2012

Abstract
We have previously demonstrated that progestin induces the rapid activation of AP-1 transcription factor and its nuclear interaction with the progesterone receptor (PR) by tethering in C4HD cells an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female Balb/c mice and in the human breast cancer line T47D. In this work, we demonstrated that MPA induces AP-1 transcriptional activation through the activation of MAPKs signaling pathways. Our recent findings have demonstrated that MPA induces the recruitment of Stat3 and PR to the GAS site in the cyclin D1 promoter. Here, we identified a novel PR/AP-1/Stat3 transcriptional complex in breast cancer cells. Cyclin D1 is a cancer-related protein whose promoter contains AP-1 binding sites (TRE sites) and Stat3 binding sites (GAS sites) in a very close proximity and lacks progesterone response elements (PRE sites). By using quantitative chromatin immunoprecipitation (ChIP) and sequential ChIP, we demonstrated that progestin induces the recruitment of c-jun, c-fos and PR to the TRE site and this recruitment is abolished when we pretreat the cells with the MAPKs inhibitor U0126. When cells were transfected with c-jun and c-fos Dominant Negatives Forms (TAM-67 and A-Fos respectively) none of these proteins are able to activate cyclin D1 promoter or are recruited to the TRE site and there is not MPA-induced Stat3 recruitment to the GAS site. In the same way when we pre-treat the cells with siRNAs against Stat3 neither c-jun, c-fos, PR or Stat3 are recruited to the AP-1 or GAS siteS in the cyclin D1 promoter. Inhibition of MPA-induced AP-1 transcriptional activation by transfection of breast cancer cells with TAM-67 and A-Fos resulted in complete abrogation of progestin-induced in vitro and in vivo breast cancer growth. Our findings reveal a novel MPA-induced PR/AP-1/Stat3 cooperative transcriptional complex in breast cancer cells. Interestingly the blockage of any of the members of the complex prevents its assembly and inhibits the MPA-induced cyclin D1 up-regulation and cell proliferation.
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 2174. doi:10.1158/1538-7445.AM2011-2174
Abstract 2186: Characterization of a novel ubiquitin E3 ligase that targets tumor suppressor RASSF1A for degradation during mitosis
Authors: Jiang Lingyan , Rong Rong , Sheikh M. Saeed , Huang Ying 
Published: June 2012

Abstract
Ras association domain family 1 isoform A (RASSF1A) is an important tumor suppressor. Loss or altered expression of RASSF1A has been associated with pathogenesis of a variety of cancers. RASSF1A is known to play an important role in regulation of mitosis, however, little is known about how RASSF1A is regulated during mitotic-phase of the cell cycle. In the present study, we have identified Cul4A as a RASSF1A E3 ligase and DDB1 serves as an adaptor protein to bring RASSF1A into the Cul4A-DDB1 complex. We have found that depletion of Cul4A E3 ligase results in increased levels of RASSF1A protein due to increased half-life; whereas overexpression of the Cul4A ligase markedly enhances RASSF1A protein ubiquitination resulting in reduced RASSF1A levels. We have further shown that Cul4A-mediated RASSF1A degradation occurs during mitosis and depletion of the E3 ligase markedly reverses mitotic-phase-stimulated RASSF1A degradation. Thus, our present study demonstrates that Cul4A is important for regulation of RASSF1A during mitosis and it may contribute to inactivation of RASSF1A thereby promoting cell cycle progression.
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 2186. doi:10.1158/1538-7445.AM2011-2186
Abstract 2187: Protocadherin 10, a novel tumor suppressor, suppresses tumorigenesis and liver metastasis of colorectal cancer cells in mice
Authors: Jao Tzu-Ming , Tsai Ming-Hong , Weng Wei-Ting , Chang Chia-Yun , Lio Hoi-Yan , Lai Yen-Chun , Yu Sung-Liang , Yang Ya-Chein 
Published: June 2012

Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer death in the world. By loss of heterozygosity approach, we identified Protocadherin 10 (PCDH10) gene with a high frequency of allelic deletion in CRC. Furthermore, the genetic alteration was associated with presence of distant metastasis and poorer overall survival of patients. Importantly, the expression of PCDH10 mRNA was silenced or downregulated in 37 (84.1%) out of 44 colorectal tumors as compared with their paired normal mucosa. We proposed that PCDH10 might be a CRC-associated tumor suppressor gene, and then investigated the biological functions of PCDH10 in CRC cells. First of all, re-expression of PCDH10 in HCT116 cells reduced cell proliferation, migration, invasion and anchorage-independent growth in vitro. Meanwhile, stable PCDH10- expressing cells (HCT116/PCDH10) exhibited suppression of tumorigenicity and liver metastasis in xenograft tumor models. In SCID mice, HCT116/PCDH10 cells with subcutaneous injection showed reduced tumor growth, and, with intrasplenic injection, showed reduced metastatic incidence and nodules in the liver, as compared with mock control cells. Taken together, these results indicate that PCDH10 is a tumor suppressor gene associated with CRC, and its downregulation might promote tumor progression and distant metastasis. In addition, allelic loss of PCDH10 gene could serve as a molecular predictor of metastasis and poor prognosis in patients with CRC.
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 2187. doi:10.1158/1538-7445.AM2011-2187