bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3036: Interaction of proliferation cell nuclear antigen (PCNA) with c-Abl in cell proliferation and response to DNA damages in breast cancer
Authors: Zhao Hua Jun , Ho Po-Chun , Lo Yuan-Hung , Espejo Alexsandra , Bedford Mark T. , Hung Mien-Chie , Wang Shao-Chun 
Published: August 2012

Abstract
Cell proliferation in primary and metastatic tumors is a fundamental characteristic of advanced breast cancer. Further understanding of the mechanism underlying enhanced cell growth will be important in identifying novel prognostic markers and therapeutic targets. Here we demonstrated that tyrosine phosphorylation of the proliferating cell nuclear antigen (PCNA) is a critical event in growth regulation of breast cancer cells. We found that phosphorylation of PCNA at tyrosine 211 (Y211) enhanced its association with the non-receptor tyrosine kinase c-Abl. We further demonstrated that c-Abl facilitates chromatin association of PCNA and is required for nuclear foci formation of PCNA in cells stressed by DNA damage as well as in unperturbed cells. Targeting Y211 phosphorylation of PCNA with a cell-permeable peptide inhibited the phosphorylation and reduced the PCNA-Abl interaction. These results show that PCNA signal transduction has an important impact on the growth regulation of breast cancer cells.
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 3036. doi:1538-7445.AM2012-3036
Abstract 3037: Cyr61/CCN1 regulates SHh through Notch signaling in pancreatic cancer cells
Authors: Haque Inamul , Majumder Monami , Banerjee Sushanta K. , Mehta Smita , Banerjee Snigdha 
Published: August 2012

Abstract
Cyr61 (cysteine-rich 61)/CCN1, a member of the CCN family of growth factors that includes CTGF, NOV, WISP-1, WISP-2 and WISP-3, is associated with the development of various cancers. Our recent studies found Cyr61/CCN1 play a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. Cyr61 mRNA and protein were detected in the early precursor lesions and their expression intensified with disease progression. However, the mode of action of CCN1 in the pancreatic carcinogenesis is unknown. In this study, we have shown that CCN1 regulates the expression of Sonic hedgehog (SHh), a lipid-modified secreted signaling protein, plays a critical role in pancreatic cancer development from Pan1N lesions to invasive growth of the disease. Moreover, we also found that SHh regulation by CCN1in pancreatic cancer cells is mediated through the regulation Notch1 signaling pathway. These extensive studies proposed that targeting Cyr61/CCN1 can provide a new treatment option for patients with pancreatic cancer as blocking CCN1 simultaneously two critical pathways (i.e., SHh and Notch1) associated with the development of the disease as well as drug resistence. (THIS WORK IS SUPPORTED BY VA MERIT GRANT TO SB).
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 3037. doi:1538-7445.AM2012-3037
Abstract 304: Proinflammatory secretory chemokine CXCL8 regulates intercellular cross-talk in the breast cancer tumor microenvironment
Authors: Jussim Casey , George Andrea L. , Rajoria Shilpi , Suriano Robert , Shanmugam Arulkumaran , Mittelman Abraham , Tiwari Raj K. 
Published: August 2012

Abstract
The cellular composition of the tumor microenvironment (TME) and soluble effector molecules mediating intercellular cross-talk are important therapeutic and preventive targets for breast cancer. Chemokines released within the TME work in a synergistic and reciprocal manner to induce malignant progression of tumor cells. CXCL8, a proinflammatory CXC chemokine shown to be released within the TME, can act as a chemoattractant, angiogenic factor, and inflammatory factor via cellular receptors CXCR1 and CXCR2. However, the specific role of CXCL8 in the signaling cascades within the tumor microenvironment has yet to be fully classified and warrants further investigation. Treatment of human breast cancer cell lines MCF-7, MDA-MB-231, and T47D with 50nM exogenous CXCL8 enhanced the expression of CXCR2. The acquisition of chemokine receptors by tumor cells, in this case CXCR2, can mediate phenotypic changes that enhance migratory and invasive potential. Treatment of these human breast cancer cell lines with 50nM exogenous CXCL8 resulted in phenotypic morphology changes characteristic of an epithelial-to-mesenchymal transition (EMT), a phenomenon commonly exhibited by metastatic tumor cells. We validated this phenomenon with 50nM exogenous CXCL8 treatment, which led to enhanced expression of both Slug (Snail2) and Twist in all three human breast cancer cell lines. Furthermore, we observed that treatment with 50nM exogenous CXCL8 promoted the migration and invasion of these breast cancer cell lines in an in vitro modified Boyden chamber assay. These results suggest that CXCL2 secreted from cells within the TME act to induce characteristic changes in human breast cancer cells, propagating the transition to more aggressive tumors. Tumor-associated macrophages (TAMs) are an important component of the heterogeneous population of cells that make up the TME. Breast cancer cells exposed to conditioned media from human monocytic cell lines THP-1 and U937, previously differentiated with 12-O-tetradecanoylphorbol-13-acetate (TPA), exhibited distinct morphology changes characteristic of EMT and enhanced migratory and invasive ability, similar to exogenous CXCL8 treatment. Together, our results suggest that CXCL8 can have profound implications in determining the fate of tumor cells by engaging in extensive cross-talk within the TME, thus providing a potential target for the treatment and prevention of breast cancer tumor progression and metastasis.
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 304. doi:1538-7445.AM2012-304
Abstract 3041: Macrophage inhibitory cytokine-1 stimulates proliferation of human umbilical vein endothelial cells by up-regulating Cyclins D1 and E through the PI3K/Akt- and ERK-dependent AP-1 and E2F activation signaling pathways
Authors: Jin Young-June , Lee Jeong-Hyung , Kim Young-Myeong , Kim Keun-Cheol , Lee Hansoo 
Published: August 2012

Abstract
Macrophage inhibitory cytokine-1 (MIC-1) is highly associated with malignant human cancers and has been suggested to be involved in tumor angiogenesis. In the present study, we examined the effect of MIC-1 on proliferation of endothelial cells. MIC-1 treatment accelerated progression of the G1 stage in cell cycle of human umbilical vein endothelial cells, together with increased cell proliferation. MIC-1 augmented the levels of cyclin D1 and E without affecting the levels of CDK inhibitors, thereby increasing activity of CDK, which led to Rb phosphorylation and subsequent E2F-1 nuclear translocation. MIC-1-induced expression of cyclins D1 and E was found to be mediated by AP-1 and E2F-1 transcription factors, and among the AP-1 members, c-Jun and JunD appeared to participate in MIC-1-mediated up-regulation of cyclin D1. Additionally, PI3K/Akt and ERK were found to mediate MIC-1-induced cyclin D1 expression. Importantly, lung endothelial cells of MIC-1 transgenic mouse exhibited increased cell proliferation rate and cyclin D1 and E levels as compared to the wild-type mouse counterparts. These results suggest that MIC-1 secreted from cancer cells stimulates endothelial cell proliferation by up-regulating of the G1 cyclins through the PI3K/Akt- and ERK-dependent AP-1 and E2F activation signaling pathways, potentially leading to the promotion of tumor angiogenesis.
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 3041. doi:1538-7445.AM2012-3041
Abstract 305: Modulation of CXCL-8 expression in human melanoma cells regulates tumor growth, angiogenesis, invasion and metastasis
Authors: Wu Sheng , Singh Seema , Kindle Scott , Varney Michelle L. , Singh Rakesh K. 
Published: August 2012

Abstract
CXCL-8, a chemokine secreted by melanoma and stromal cells, serves as a growth and angiogenic factor for melanoma progression. This study evaluated how modulation of CXCL-8 levels in melanoma cell lines with different tumorigenic and metastatic potentials affected multiple tumor phenotypes. A375P cells (CXCL-8 low expressor) were stably transfected with a CXCL-8 mammalian expression vector to overexpress CXCL-8, whereas A375SM cells (CXCL-8 high expressor) were transfected with a CXCL-8 antisense expression vector to suppress CXCL-8 expression. Subsequent cell proliferation, migration, invasion, and soft-agar colony formation were analyzed and in vivo tumor growth and metastasis were evaluated using mouse xenograft models. Our data demonstrate that over-expression of CXCL-8 significantly enhanced primary tumor growth and lung metastasis, accompanied by increased microvessel density in vivo, as compared to vector control transfected cells. We also observed increased colonogenic ability, growth and invasive potential of CXCL-8 over-expressing cells in vitro. Knock-down of CXCL-8 using an antisense vector resulted in increased cell death and reduced tumor growth relative to control. Taken together, these data confirm that CXCL-8 expression plays a critical role in regulating multiple cellular phenotypes associated with melanoma growth and metastasis.
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 305. doi:1538-7445.AM2012-305
Abstract 3050: Inducing apoptosis in mantle cell lymphoma using inhibitors of cyclin-dependent kinases and the Bcl-2 inhibitor ABT-737
Authors: Lo Wann-Cheng , LeBrun David P. , Greer Peter A. 
Published: August 2012

Abstract
Mantle cell lymphoma (MCL) is a cyclin D1 over-expressing B cell lymphoma which displays unregulated cell cycle progression driven by increased cyclin-dependent kinase (CDK) activity. We are investigating selective small molecule CDK inhibitors as potential therapeutics in MCL. AZD5438, flavopiridol, PD-0332991 and SNS-032 have distinct efficacies against different groups of CDKs. We hypothesize that inhibiting CDK-7 and -9 will be more effective in causing cell death in MCL than inhibiting CDK-1,-2,-4 and- 6. In Jeko-1 cells, AZD5438 and flavopiridol displayed time- and dose-dependent inhibition of cell proliferation, inhibition of the phosphorylation of CDK substrates, and G1 cell cycle arrest; while PD-0332991 showed a strong cytostatic effect by inhibiting cell proliferation and arresting cells at the G1 phase, but not inducing apoptosis to the same extent as flavopiridol and AZD5438. In addition, AZD5438, flavopiridol and SNS-032 induced caspase-3 activation and down regulation of Mcl-1, but no apoptotic effect was shown in PD-0332991 treated cells. These differential effects may be associated with essential survival functions conferred by genes regulated by CDK7/9 including the pro-survival protein Mcl-1. However, there were no apoptotic effects observed with any of these CDK inhibitors in Granta-519 cells, which may due to high Bcl-2 levels. We are now exploring combinations of CDK7/9 inhibitors with a small molecule inhibitor of Bcl-2 function. We expect CDK7/9 inhibition will reduce Mcl-1 expression at the transcriptional level and thereby sensitize both Jeko-1 and Granta-519 cells to Bcl-2 inhibition. We will also investigate Mcl-1 and Bcl-2 levels in clinical samples to see if there is a correlation with outcomes. Our expectation is that Mcl-1/Bcl-2 levels may ultimately become a useful prognostic and predictive biomarker in MCL.
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 3050. doi:1538-7445.AM2012-3050
Abstract 3056: High levels of Wee1 are associated with malignancy and has potential as a therapeutic target in malignant melanoma
Authors: Magnussen Gry I. , Emilsen Elisabeth , Rosnes Anne K. , Flørenes Vivi Ann 
Published: August 2012

Abstract
Malignant melanoma is the most increasing form of cancer worldwide, in addition to being the second most common cancer in young adults. Whereas the prognosis is good when detected early, there are no curative treatments once the cancer has spread (stage IV). Thus, there is a precarious need for new and more effective treatment options. Since the G1/S checkpoint of the cell cycle is dysfunctional in the majority of human cancers, the G2/M transition has been a focus of attention for targeted therapy the recent years. The Wee1 kinase is a major regulator of the G2/M checkpoint, and may halt the cell cycle by adding a negative phosphorylation on CDK1 (Tyr15). Additionally, Wee1 has a function in safeguarding the genome integrity during DNA synthesis. To assess the role of Wee1 in the progression of malignant melanoma we examined its expression in a panel of paraffin-imbedded patient derived tissues of benign nevi, primary- and metastatic melanoma. We found that Wee1 expression increased in the direction of malignancy, and had a strong, positive correlation with known markers of proliferation: Cyclin A (p&lt;0.0001), Ki67 (p&lt;0.0001), Cyclin D3 (p&lt;0.001), p21Cip1/WAF1 (p=00.3), p53 (p&lt;0.025), thicker primary tumours (p=0.001), ulceration (p=0.005) and poor disease-free survival (p=0.008). Transfections using siWee1 in three metastatic melanoma cell lines; WM239WTp53, WM45.1MUTp53 and LOXWTp53, further support our hypothesis of a tumour promoting role of Wee1 in melanomas. Whereas no effect was observed in LOX cells, transfection with siWee1 led to accumulation of cells in G1/S and S phase of the cell cycle in WM239 and WM45.1 cells, respectively. Both latter cell lines displayed reduced viability (MTS analysis), DNA damage (γ-H2AX) and induction of apoptosis (DNA fragmentation, caspase 3- and PARP-cleavages), in the absence of Wee1. Thus, the effect of silencing Wee1 may not be solely dependent of the p53 status of the cells. Moreover, our preliminary results have demonstrated that combined inhibition of Wee1 using (Wee1 inhibitor II/681641) and MAPK/ERK signalling (PD98059) further enhanced the therapeutic effect, as compared to Wee1 silencing alone. Together these results reveal the importance of Wee1 as a prognostic biomarker in melanomas and indicate that targeting Wee1 alone or in combination with other targeted therapies or conventional radio- or chemotherapy may be a promising approach in the treatment of melanoma 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 3056. doi:1538-7445.AM2012-3056
Abstract 3057: CDK5 modulates the cell cycle, apoptosis and paclitaxel sensitivity in human ovarian cancer cells with wild-type p53 function
Authors: Zhang Shu , Mao Weiqun , Ahmed Ahmed A. , Li Zong-Fang , Le Xiao-Feng , Bast Robert C. 
Published: August 2012

Abstract
Cyclin-dependent kinase 5 (CDK5) is a ubiquitously expressed serine/threonine kinase that was initially identified in bovine brain extracts and plays an important role in normal neuron development and neurodegenerative diseases. This molecule has recently been shown to possess many cellular functions in non-neuronal tissues as well. Using a kinome siRNA screen, we identified CDK5 as a kinase that modulates paclitaxel sensitivity in human ovarian cancer cells. The aim of this report is to identify mechanisms by which CDK5 regulates paclitaxel sensitivity in human ovarian cancer cells. Despite nucleotide sequence homology with human CDK1, a role of CDK5 in regulating the cell cycle remains unclear. Here we demonstrate dual roles of CDK5 in regulating the cell cycle and apoptosis. We have found that knockdown of CDK5 with multiple siRNAs markedly inhibits cell proliferation and increases paclitaxel sensitivity in several p53 wild type ovarian cancer cell lines using assays for cell viability and clonogenic growth. CDK5 knockdown with or without paclitaxel treatment induces G1 arrest of the cell cycle and apoptotic cell death linked to a significant induction of p53, p21Cip1 and p27Kip1 proteins. Induction of G1 arrest following CDK5 knockdown depends on induction of p21Cip1 and p27Kip1, since silencing p21Cip1 and/or p27Kip1 dramatically reduces CDK5 knockdown-induced G1 arrest. A CDK5 knockdown-induced increase of p53 expression contributes both to CDK5 knockdown-induced G1 arrest and to apoptosis, as silencing p53 markedly diminishes CDK5 knockdown-induced G1 arrest and apoptosis. As expected, a CDK5 knockdown-induced increase in p21Cip1 expression depends on p53-mediated transcriptional activation demonstrated by QRT-PCR and reporter luciferase assays. CDK5 knockdown activates caspase-3 and a pan-caspase inhibitor completely blocks CDK5 knockdown-induced apoptosis. Significant Inhibition of Bcl-2 expression is found in CDK5 knockdown-induced apoptosis and additional inhibition of Bcl-2 expression is found with combined CDK5 and paclitaxel treatment. Taken together, these data suggest that CDK5 can modulate paclitaxel sensitivity through regulating both the cell cycle and apoptosis. CDK5 inhibition can potentiate paclitaxel activity in human ovarian cancer cells with wild-type p53 function, providing a novel approach for enhancing the efficacies of paclitaxel-based regimens for low grade ovarian cancer in the clinic.
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 3057. doi:1538-7445.AM2012-3057
Abstract 3058: Mad1 Serine-214 phosphorylation is essential for the spindle assembly checkpoint
Authors: Yang Chunying , Guo Xiaojing , Hao Jianwei , Wang Haibo , zhang wei , xu Bo 
Published: August 2012

Abstract
The spindle assembly checkpoint (SAC), which blocks anaphase onset until all chromosomes have bioriented, is one of the key self-monitoring systems of the eukaryotic cell cycle. The mitotic arrest-deficient protein 1 (Mad1), a critical component of the SAC, is hyperphosphorylated in mitosis. However, the kinases responsible for Mad1 phosphorylation and its functional significance are not fully understood. Here we report that Mad1 is phosphorylated on Serine-214 in vivo and in vitro by the ATM kinase, a critical DNA damage response protein also activated in mitosis and required for the SAC. This phosphorylation facilitates the homodimerization of Mad1 and heterodimerzation with Mad2. Cells expressing the mutation of Serine-214 to Alanine show a defective SAC and shorter mitotic timing. Introduction of the Serine-214 to glutamic acid mutant Mad1 partially complements the SAC defect in ATM-deficient cells. Immunofluorescence experiments show that Mad1-Ser214 phosphorylation has a similar localization pattern to ATM Serine-1403 phosphorylation during mitosis. In clinical samples, we find that Mad1 Serine-214 phosphorylation is highly expressed in malignant breast cancer tissues and is significantly correlated with the mitotic index (p&lt;0.001, Pearson Correlation Test), indicating the physiological significance of Mad1 Serine-214 phosphorylation. Together, these findings reveal an important role of ATM-mediated Mad1 phosphorylation in mitosis.
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 3058. doi:1538-7445.AM2012-3058
Abstract 306: TWEAK functions as chemotactic factor for glioma cells via Lyn activation
Authors: Dhruv Harshil D. , Jameson Nathan , Patel Falak , Nakada Mitsutoshi , Armstrong Brock , Winkles Jeffrey A. , Berens Michael E. , Tran Nhan L. 
Published: August 2012

Abstract
The long-term survival of patients with glioblastoma multiforme is compromised by the tumor's proclivity for local invasion into the surrounding normal brain. These invasive cells escape surgery and display resistance to chemotherapeutic- and radiation-induced apoptosis. We have previously shown that tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion and survival via binding to the fibroblast growth factor-inducible 14 (Fn14) receptor and subsequent activation of the Rac1/NF-kappaB pathway. In addition, we have reported previously that Fn14 is expressed at high levels in migrating glioma cells in vitro and invading glioma cells in vivo. Here we demonstrate that TWEAK can act as a chemotactic factor for glioma cells, a potential process to drive cell invasion into the surrounding brain tissue. Specifically, we detected a chemotactic migration of glioma cells to the concentration gradient of TWEAK using the Modified Boyden chamber assay. Because TWEAK has been shown to be expressed in normal astrocytes, microglia, and endothelial cells, we neutralized TWEAK using a recombinant soluble murine Fn14-Fc decoy receptor and examined the effect on glioma cell invasion in the ex vivo rat brain slice model. Incubation of the brain slice with the Fn14-Fc decoy receptor reduced glioma cell invasion as compared to control IgG treated brain slice. Since Src family kinases (SFK) have been implicated in chemotaxis, we next determined whether TWEAK:Fn14 engagement activated these cytoplasmic tyrosine kinases. Our data shows that TWEAK stimulation of glioma cells results in a rapid phosphorylation of Src as detected by Western blot analysis using a pan-Src phosphorylation antibody. To determine which SFK member is phosphorylated by TWEAK, we applied the multiplex Luminex assay and identified Lyn as a candidate SFK. Immunoprecipitation of Lyn from TWEAK-treated cells verified that Lyn is phosphorylated as determined by phosphotyrosine immunoblot analysis. Immunodepletion of Lyn by siRNA oligonucleotides suppressed the chemoattractive effect of TWEAK on glioma cells. We hypothesize that TWEAK secretion by cells present in the glioma microenvironment induce invasion of glioma cells into the brain parenchyma. Understanding the function and signaling of the TWEAK-Fn14 ligand-receptor system may lead to development of novel therapies to therapeutically target invasive glioma cells.
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 306. doi:1538-7445.AM2012-306