bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4073: Proteasomal degradation of JunD is required for TGF-β induced inhibition of proliferation in prostate cancer cells.
Authors: Millena Ana C. , Vo BaoHan T. , Strong Nicole , Walker Lindsey , Cao Yang , Klueva Natalya , Pfarr Curt , Khan Shafiq 
Published: August 2014

Abstract
Transforming growth factor-β (TGF-β) inhibits proliferation of prostate epithelial cells. However, prostate cancer cells in advanced stages become resistant to TGF-β effects on proliferation. In this study, we have investigated the role of AP-1 family of transcription factors, specifically the Jun family members (c-Jun, JunB and JunD) in TGF-β1 effects on prostate cancer cell proliferation. Basal expression of individual Jun family members was determined by RT-PCR and Western blot analysis in four prostate cell lines: RWPE1, LNCaP, DU145 and PC3 cells. Jun levels were also examined in response to TGF-β1. c-Jun was expressed in all cell lines and its expression was up-regulated by TGF-β1. Levels of JunB were higher in normal cells compared to those in cancer cells and TGF-β1caused an increase in JunB levels. JunD levels were higher in all cell lines; TGF-β1 had differential effects on JunD protein levels. While it caused a significant decrease in JunD levels in RWPE-1 and DU145 cells, it did not affect JunD levels in PC3 cells. These differential effects on JunD levels correlated with differential effects of TGF-β on cell proliferation. Individual Jun family members were overexpressed in DU145 cells and effects on cell proliferation were determined. Over-expression of c-Jun and JunB decreased proliferation rate in DU145 cells; however, overexpression of JunD increased proliferation in these cells. Interestingly, cells over-expressing JunD still succumb to inhibitory effect of TGF-β1 after six to eight days of incubation. Furthermore, silencing JunD by siRNA decreased proliferation in both DU145 and PC3 cells. To determine the molecular mechanism of TGF-β-induced down-regulation of JunD, we pretreated cells over-expressing JunD with a proteosomal inhibitor, MG132. Pretreatment of MG132 blocked the degradation of JunD in in DU145 cells over-expressing JunD. In conclusion, our studies show that specific Jun family exerts differential effects on proliferation in prostate cancer cells in response to TGF-β1. While c-Jun and Jun B mediate the inhibitory effects of TGF-β1 on proliferation, JunD counteracts these effects. TGF-β1 causes inhibition in proliferation by degrading JunD via proteasomal degradation.
Acknowledgements: These studies were supported by the NIH/NIMHD/RCMI grant #G12MD007590, NIH/NIMHD #5P20MD002285, and DOD grant # W8I-08-1-0077.
Citation Format: Ana C. Millena, BaoHan T. Vo, Nicole Strong, Lindsey Walker, Yang Cao, Natalya Klueva, Curt Pfarr, Shafiq Khan. Proteasomal degradation of JunD is required for TGF-β induced inhibition of proliferation in prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4073. doi:10.1158/1538-7445.AM2013-4073
Abstract 4074: Transcription factors involved in the genesis and progression of cancer differently modulated by transforming growth factor-beta3 (TGF-Beta3) in prostate cell lines.
Authors: Caggia Silvia , Candido Saverio , Libra Massimo , Cardile Venera 
Published: August 2014

Abstract
Transforming growth factor-beta3 (TGF-β3) is a member of a family of multifunctional cytokines that control different cellular processes including cell proliferation, morphogenesis, migration, extracellular matrix production, cytokine secretion, and apoptosis, as well as in normal physiological and disease processes. Among the various isoforms of TGF-β, TGF-β1 has been the most studied form, especially in the context of tumor development. In contrast, only few studies have been focused on the role of TGF-β3 in tumorogenesis. Recently, it has been shown that the transcription factors Yin Yang 1 (YY1) is involved in the TGF-β3 pathway. YY1 is known to be associated with cancer progression. One the potential mechanisms of this association is linked with the inactivation of p53. On this ground, the aims of this study were i) to explore the correlated expression of p53 and YY1 in a human benign prostate hyperplasia cell line (BPH-1) and in two prostate cancer cell lines, LNCaP (androgen-sensitive) and DU-145 (androgen-refractory) after treatment with different dose of TGF-β3; ii) to determine, in TGF-β3-treated prostate cell lines, the expression of a fraction of intracellular signalling pathways involved in both cell cycle progression and in apoptosis. TGF-β3 stimulation in prostate cancer cell lines showed different effects, such as YYI downregulation and p53 overexpression. These effects are also associated with a different modulation of intracellular signaling pathways (PI3K, AKT, pAKT, PTEN, Bcl-2, Bax, and iNOS). In conclusion, these findings may have important therapeutic implications in prostate cancer.
Citation Format: Silvia Caggia, Saverio Candido, Massimo Libra, Venera Cardile. Transcription factors involved in the genesis and progression of cancer differently modulated by transforming growth factor-beta3 (TGF-Beta3) in prostate cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4074. doi:10.1158/1538-7445.AM2013-4074
Abstract 4079: Control of survivin expression by IGF-I in prostate epithelial cells.
Authors: Danielpour David , Song Kyung , Shankar Eswar , Yang Jiayi , Bane Kara L. 
Published: August 2014

Abstract
Survivin, a unique member of the inhibitor of apoptosis (IAP) proteins, is overexpressed in numerous cancers through poorly defined mechanisms. We show that insulin-like growth factor-I (IGF-I), which is implicated in the etiology of prostate cancer, induces the expression of Survivin in a variety of pre-neoplastic and malignant prostate cell lines. Using the pre-neoplastic NRP-152 rat prostate cell line as a model, we showed that silencing Survivin by lentiviral-mediated shRNA represses IGF-I-stimulated cell growth, suggesting that the induction of Survivin is critical to this growth response. Moreover, we show that IGF-I induces the expression of Survivin through a transcriptional mechanism that is mediated in part by the PI3K/Akt/mTORC1 pathway. The CDE and CHR response elements in the proximal region of the Survivin promoter are decisive for this IGF-I response. TGF-β signaling antagonists similarly induced this promoter activity and rendered cells refractory to further promoter activation by IGF-I. Suppression of TGF-β signaling, either by TGF-β receptor kinase inhibitors or by silencing Smads 2 and 3, induced Survivin expression and promoted cell growth similar to that induced by IGF-I. TGF-β receptor antagonists also rescued cells from down-regulation of Survivin expression and growth suppression by pharmacological inhibitors of PI3K, Akt, MEK and mTORC1. Sh-RNA gene silencing studies suggest that mTORC1 induces while mTORC2 represses the expression of Survivin. We conclude that IGF-I signaling through a PI3K/Akt/mTORC1-dependent mechanism elevates expression of Survivin and promotes growth of prostate epithelial cells by suppressing Smad-dependent autocrine TGF-β signaling.
Citation Format: David Danielpour, Kyung Song, Eswar Shankar, Jiayi Yang, Kara L. Bane. Control of survivin expression by IGF-I in prostate epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4079. doi:10.1158/1538-7445.AM2013-4079
Abstract 408: Hematogenous metastasis in ovarian cancer: Importance of the ErbB3/NRG axis.
Authors: Pradeep Sunila , Wook Kim , Nishimura Masato , Raghavan Pradeep , Pecot Chad , Lopez Gabriel , Fidler Isaiah , Sood Anil 
Published: August 2014

Abstract
Background: Ovarian cancer is predominantly thought to metastasize by intraperitoneal spread. Here, we report unexpected findings related to hematogenous ovarian cancer metastasis with strong tropism for the omentum.
Study methods and results: To investigate the potential patterns of metastasis from circulating ovarian cancer cells, we established a novel parabiosis model, where 2 mice are surgically fused to allow a common circulation. Using this model, we found that ovarian cancer cells can indeed metastasize hematogenously and predominantly localize to the omentum. Cells propagated from this model are called SKOV3-OM3. To understand potential mechanisms, we carried out integrated genomic and human Phospho RTK arrays, which pointed to ErbB3/NRG1 as a dominant activated pathway. NRG1 stimulated migration (40%) and invasion (60%) of SKOV3-OM3 cells. NRG1 stimulation consistently induced downstream signaling pathways such as PI3K-AKT axis and Src activation in the cells with predilection for omental metastasis. We also showed that EMT modulating genes (eg. Vimentin and E-cadherin) are regulated by ErbB3 and PI3K in SKOV3-OM3 cells. In parallel approaches to determine the requirement of the ErbB3/NRG1 pathway for hematogenous metastasis of ovarian cancer to the omentum, both immune-deficient and immune-competent models were used. Upon intracardiac (IC) injection of SKOV3-OM3 cells (nude mice) and IG10-OM2 cells (C57BL/6 mice), tumor development and metastasis was followed by weekly luciferase imaging; tumors were harvested for histopathology and downstream molecular analyses. ErbB3 silencing using siRNA incorporated in DOPC nanoliposomes resulted in substantially decreased tumor growth and metastasis compared with control siRNA in both models (P &lt;0.001). ErbB3 silencing resulted in significant reduction of proliferation and increase in apoptosis for both experiments. These data indicate that ErbB3 plays a functionally significant role in omental metastasis.
Conclusion: This study provides a new paradigm regarding ovarian cancer metastasis in that ovarian cancer cells have a parallel path of spread to the omentum hematogenously. As such, these findings have significant clinical implications.
Citation Format: Sunila Pradeep, Kim Wook, Masato Nishimura, Pradeep Raghavan, Chad Pecot, Gabriel Lopez, Isaiah Fidler, Anil Sood. Hematogenous metastasis in ovarian cancer: Importance of the ErbB3/NRG axis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 408. doi:10.1158/1538-7445.AM2013-408
Abstract 4080: TGF-β Effects on prostate cancer cell migration are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway.
Authors: Vo Baohan T. , Morton Derrick , Komaragiri Shravan , Millena Ana C. , Khan Shafiq A. 
Published: August 2014

Abstract
Transforming growth factor-beta (TGF-β) plays an important role in the progression of prostate cancer. It exhibits both tumor suppressor and tumor promoting activities. Correlations between COX-2 overexpression and enhanced production of PGE2 have been implicated in cancer progression; however, there are no studies indicating that TGF-β effects in prostate cancer cells involve PGE2 synthesis. In this study, we investigated TGF-β regulation of COX-1 and COX-2 expression in prostate cancer cells and whether the effects of TGF-β on cell proliferation and migration are mediated by PGE2. COX-1 protein was ubiquitously expressed in prostate cells; however, COX-2 protein levels were only detected in prostate cancer cells. TGF-β treatment increased COX-2 protein levels and PGE2 secretion in PC3 cells. Exogenous PGE2 and PGF2α had no effects on cell proliferation in LNCaP, DU145, and PC3 cells while PGE2 and TGF-β induced migratory behavior only in PC3 cells. Only EP2 and EP4 receptors were detected at mRNA levels in prostate cells. The EP4-targeting siRNA inhibited PGE2 and TGF-β-induced migration of PC3 cells. PGE2 and TGF-β induced phosphorylation of AKT which was blocked by antagonists of PGE2 (EP4) receptors (L161982, AH23848) and PI3-kinase inhibitor (LY294002) in PC3 cells. Pretreatment with L161982 or AH23848 blocked the stimulatory effects of PGE2 and TGF-β on cell migration, while LY294002 or rapamycin completely eliminated PGE2, TGF-β, and EGF-induced migration PC3 cells. We conclude that TGF-β increases COX-2 levels and PGE2 secretion in prostate cancer cells which, in turn, mediates TGF-β effects on cell migration through the activation of PI3K/AKT/mTOR pathway.
Acknowledgements: These studies were supported by the NIH/NIMHD/RCMI grant #G12MD007590, NIH/NIMHD #5P20MD002285, and DOD grant # W8I-08-1-0077.
Citation Format: Baohan T. Vo, Derrick Morton, Shravan Komaragiri, Ana C. Millena, Shafiq A. Khan. TGF-β Effects on prostate cancer cell migration are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4080. doi:10.1158/1538-7445.AM2013-4080
Abstract 4096: FAK inhibition with small molecule inhibitor Y15 decreases viability in thyroid cancer cell lines.
Authors: O'Brien Shalana B. , Golubovskaya Vita M. , Cance William G. 
Published: August 2014

Abstract
Introduction: Thyroid cancer is the most common endocrine malignancy and papillary the most common subtype. While low stage papillary carcinomas are treatable, for nonresectable tumors that do not respond to iodine, a treatment is still needed. In comparison, for advanced medullary cancer, a tyrosine kinase inhibitor, Vandetanib, is currently being used. Focal Adhesion Kinase (FAK) is a tyrosine kinase involved in many protein-protein interactions that control important cellular functions. FAK is upregulated in many cancer cell lines, including thyroid. It contains an autophosphorylation site Y397, which is blocked by 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15), a small molecule FAK inhibitor. We propose that this inhibitor, Y15, will decrease viability of thyroid cancer cell lines.
Methods: Four human thyroid cancer cell lines were cultured in vitro. K1, BCPAP, and TPC1 were derived from papillary thyroid carcinomas, and TT was derived from a medullary thyroid carcinoma. Western blots were used to detect expression of FAK and pY397 FAK in each untreated line. These were repeated with differing concentrations of Y15 plus the Novartis FAK inhibitor TAE226 as a positive control. MTS assays of each cell line were used to measure cell viability with increasing doses of Y15. Untreated medium, DMSO, and TAE226 were used as negative and positive controls.
Results: All untreated thyroid cancer cell lines expressed FAK and phosphorylated Y397 FAK on Western blotting. Increasing doses of Y15 in Western blotting decreased the expression of pY397 FAK in all cell lines. This was also associated with increased cell detachment. In MTS assays, viability was also decreased with Y15 in a dose-dependent manner across all cell lines. Significant inhibition was reached at relatively low doses: there was a 90% decrease in viability with 10μM Y15 in TPC1 cells and 5μM Y15 in TT cells. The effects were seen across all lines, but most profound in TPC1 and TT.
Conclusions: Papillary thyroid cancer cell lines and medullary carcinoma cells express FAK and pY397. The FAK inhibitor Y15 causes a dose-dependent decrease of phosphorylated FAK, and this disruption decreases cell viability. Our data suggests Y15 may be an effective potential treatment for advanced papillary thyroid cancer.
Citation Format: Shalana B. O'Brien, Vita M. Golubovskaya, William G. Cance. FAK inhibition with small molecule inhibitor Y15 decreases viability in thyroid cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4096. doi:10.1158/1538-7445.AM2013-4096
Abstract 4100: YM-155 sensitizes malignant human glioma cells to ABT-737 via survivin and Mcl-1 downregulation in an EGFR-dependent context.
Authors: Jane Esther P. , Premkumar Daniel , DiDomenico Joseph , Hu Bo , Cheng Shi-Yuan , Pollack Ian 
Published: August 2014

Abstract
Antiapoptotic proteins are commonly overexpressed in gliomas, contributing to therapeutic resistance. We recently showed that clinically achievable concentrations of the Bcl-2/Bcl-xL inhibitor ABT-737 failed to induce apoptosis in glioma cells, with persistent expression of survivin and Mcl-1. To address the role of these mediators in glioma apoptosis resistance, we analyzed the effects of YM-155, a survivin suppressant, on survival on a panel of glioma cell lines. YM-155 inhibited growth, and downregulated survivin and Mcl-1 in a dose- and cell line-dependent manner. Whereas U373, LN18, LNZ428, T98G, LN229, and LNZ308 cells exhibited an IC50 of 10-75 nM, A172 cells were resistant (IC50 ∼ 250 nM). No correlation was found between sensitivity to YM-155 and baseline expression of survivin or cIAP-1/cIAP-2/XIAP. However, strong correlation was observed between EGFR activation levels and YM-155 response, which was confirmed using EGFR-transduced versus wild-type cells. Because we postulated that decreasing Mcl-1 expression may enhance glioma sensitivity to ABT-737, we examined whether cotreatment with YM-155 promoted ABT-737 efficacy. YM-155 synergistically enhanced ABT-737-induced cytotoxicity and caspase-dependent apoptosis. Down-regulation of Mcl-1 using shRNA also enhanced ABT-737-inducing killing, confirming an important role for Mcl-1 in mediating synergism between ABT-737 and YM-155. As with YM-155 alone, sensitivity to YM-155 and ABT-737
Citation Format: Esther P. Jane, Daniel Premkumar, Joseph DiDomenico, Bo Hu, Shi-Yuan Cheng, Ian Pollack. YM-155 sensitizes malignant human glioma cells to ABT-737 via survivin and Mcl-1 downregulation in an EGFR-dependent context. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4100. doi:10.1158/1538-7445.AM2013-4100
Abstract 4102: FAT1: A novel regulator of cancer and inflammation.
Authors: Dikshit Bhawana , Chattopadhyay Parthaprasad , Sinha Subrata , Chosdol Kunzang 
Published: August 2014

Abstract
FAT1, a member of cadherin superfamily is a large trans-membrane protein with 34 cadherin repeats. FAT1 was originally identified as a tumor suppressor gene in Drosophila but its role in human cancers is just beginning to unfold. Considering its tumor suppressive role in Drosophila, few studies have reported similar function of FAT1 in human cancers but on the contrary several studies have also demonstrated oncogenic role of FAT1. In this study we identified oncogenic role of FAT1 in human glioma where knockdown of FAT1 was found to inhibit migration and invasion of glial cells. Further investigation into molecular mechanism of FAT1 function revealed direct link to AP-1 mediated transcription via Programmed Cell Death 4 (PDCD4). Knockdown of FAT1 was found to inhibit AP-1 mediated transcription and expression of downstream target genes. AP-1 is a known mediator of cancer and inflammation and accordingly we found decreased expression of several pro-inflammatory markers like COX-2, cytokines like IL-6, IL-1β and chemokines like IL-8, MCP-1 and MIP-2 after FAT1 knockdown. Interestingly, the expression of anti-inflammatory cytokine IL-10 was found to be increased after FAT1 knockdown. Moreover FAT1 expression was also found to positively correalate with COX-2 and IL-6 expression in primary GBM tumors. Thus, in this study FAT1 was found to act as an oncogene as well as to orchestrate the inflammatory milieu of the glioma cells by regulating AP-1 mediated transcription via PDCD4.
Citation Format: Bhawana Dikshit, Parthaprasad Chattopadhyay, Subrata Sinha, Kunzang Chosdol. FAT1: A novel regulator of cancer and inflammation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4102. doi:10.1158/1538-7445.AM2013-4102
Abstract 4104: Netrin-1 promotes the invasiveness and survival of human glioblastoma cells.
Authors: Keski-Oja Jorma K. , Ylivinkka Irene , Hu Yizhou , Nyman Tuula , Hyytiainen Marko 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is the most severe human brain cancer, which has no efficient treatment. The main reason for the lethality of GBM is its resistance to all current therapies and highly invasive. According to microarray data on Oncomine database netrin-1 is upregulated in glioblastoma tumors. Netrin-1 is a secreted laminin related extracellular matrix protein. Its main function is to regulate the axon guidance during embryogenesis. Recently it has been observed to act as a survival factor for different forms of cancer such as aggressive neuroblastoma, metastatic breast cancer and non small cell lung cancer. It also promotes tumorigenesis of colorectal cancer.
Based on these observations we explored the possibility whether netrin-1 plays a role in human GBM. We analyzed the effects of netrin-1 expression on human GBM cells. According to Matrigel invasion assays overexpression of netrin-1 increased the invasiveness whereas partial knock-down of netrin-1 by shRNAs reduced the invasiveness of human GBM cells. On the other hand, complete knock-down of netrin-1 led to apoptotic death of those cells. To further analyze netrin-1 signaling in human GBM we performed a mass spectrometry screen to identify binding partners of netrin-1. We identified Notch as a novel receptor for netrin-1. In addition, we observed that netrin-1 overexpression increased and knockdown decreased Notch activation. The role of Notch signaling regarding the aggressiveness of various cancers has been controversial. Our results confirm that increased Notch signaling increases glioblastoma cell invasiveness, and that netrin-1 increases Notch signaling. Further, we identified here a recombinant netrin-1 fragment that inhibits Notch signaling by blocking the Notch signaling complex to the cell surface.
Current studies provide new mechanistic information on the tumorigenesis of GBM. Activation of Notch signaling pathway has been linked to the initiation of EMT which is essential for cancer cell invasion. Our results suggest that netrin-1 regulates GBM invasion by activating Notch signaling. The inhibition of netrin-1 signaling may prove out to be a treatment option for human glioblastoma.
Citation Format: Jorma K. Keski-Oja, Irene Ylivinkka, Yizhou Hu, Tuula Nyman, Marko Hyytiainen. Netrin-1 promotes the invasiveness and survival of human glioblastoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4104. doi:10.1158/1538-7445.AM2013-4104