bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4272: Suppression of epigenetic regulator NURF leads to autophagy mediated chemo-and immune sensitization of triple negative breast cancer
Authors: Tyutyunyk Liliya , Gewirtz David A. , Landry Joseph , Dao Nga 
Published: August 2019

Abstract
Dysregulation of the epigenome is implicated in initiation and progression of variety of cancers and their acquired resistance to chemotherapy. As such, targeting epigenetic regulators has the potential to modulate tumor cell biology and reestablish tumor cell sensitivity to chemotherapy and/or radiation. Our studies demonstrate that silencing of the epigenetic regulator Nucleosome Remodeling Factor (NURF) sensitizes breast tumor cells to chemotherapy and enhances the anti-tumor immune response. Compared to controls, NURF KD 4T1 breast tumor cells exposed to doxorubicin (Dox) show increased DNA damage (gamma H2AX staining) and autophagy (acridine orange staining) in vitro and enhanced growth inhibition both in vitro and in vivo. NURF KD also sensitizes 4T1 cells to doxorubicin stimulated Natural Killer (NK) cell antitumor activity ex vivo, which is associated with a cytokine/chemokine secreted by doxorubicin exposed NURF KD cells; potential candidates are CCL5, TNFa and CCL2. The importance of NK cells for the enhanced growth control of doxorubicin treated NURF KD cells was confirmed using a mAb depletion approach. Autophagy may be instrumental in NK cell activation and elimination of tumor cell targets by mediating cytokine secretion. Sensitization of NURF KD 4T1 cells to doxorubicin, both increased autophagy and enhanced NK cell activity, were also observed using a small molecule inhibitor of NURF, suggesting that NURF can also be targeted pharmacologically. Our studies suggest that enhanced doxorubicin induced DNA damage and autophagy (cell autonomous effects) and NK cell cytotoxic activity (cell non-autonomous affects) may be primary contributors to immune sensitization in NURF KD cells. Increased cell autonomous antitumor effects by doxorubicin in concert with increased cell non-autonomous immunogenicity could help to achieve tumor regression, reduce metastasis, and possibly promote long term remission in breast cancer.
Citation Format: Liliya Tyutyunyk, David A. Gewirtz, Joseph Landry, Nga Dao. Suppression of epigenetic regulator NURF leads to autophagy mediated chemo-and immune sensitization of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4272.
Abstract 4280: The cycloartane triterpenoid ADCX impairs autophagic degradation through Akt overactivation and promotes apoptotic cell death in multidrug-resistant HepG2/ADM cells
Authors: YAO NAN , Sun Haiyan , Huang Maohua , Ye Wencai , Chen SiBao , Zhang Dong-Mei 
Published: August 2019

Abstract
Multidrug resistance is the main obstacle in cancer chemotherapy. Emerging evidence has demonstrated the important role of autophagy in cancer cell resistance to chemotherapy. Therefore, autophagy inhibition may be a promising strategy for conquering drug resistance in liver cancer cells.
Methods: HepG2/ADM cells were treated with ADCX in the presence or absence of relevant inhibitors, apoptosis was measured by flow-cytometry and expression of autophagy and apoptosis related proteins was detected by western blotting. Confocal microscope was used for GFP-LC3 assay, tandem mRFP-GFP-LC3 assay, DQ-BSA method and colocalization of GFP-LC3 and LAMP1. Celluar ultrastructure was observed by transmission electronic microscopy.
Results: ADCX, a natural cycloartane triterpenoid extracted from the traditional Chinese medicine (TCM) source Cimicifugae Rhizoma (Shengma), inhibited autophagic degradation by impairing the maturation of lysosomal cathepsins in multidrug resistant liver cancer HepG2/ADM cells, thereby leading to autophagic flux inhibition. Interestingly, Akt was over-activated by ADCX treatment, which was associated with impairment of cathepsin maturation. Moreover, impairing autophagic degradation promoted ADCX-induced apoptotic cell death in HepG2/ADM cells.
Conclusions: Our study indicates that impairing autophagic degradation may be an effective approach for overcoming resistance and also suggests a novel role for Akt in autophagic degradation.
Citation Format: NAN YAO, Haiyan Sun, Maohua Huang, Wencai Ye, SiBao Chen, Dong-Mei Zhang. The cycloartane triterpenoid ADCX impairs autophagic degradation through Akt overactivation and promotes apoptotic cell death in multidrug-resistant HepG2/ADM cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4280.
Abstract 4286: TGFβ induced SMAD4 dependent apoptosis proceeded by EMT in colorectal cancer
Authors: Poyil Pratheeshkumar , Siraj Abdul K. , Padmaja Divya Sasidharan , Parvathareddy Sandeep Kumar , Bu Rong , Masoodi Tariq , Kong Yan , Thangavel Saravanan , Ahmed Saeeda Omer , Al-Sanea Nasser , Ashari Luai H. , Abduljabbar Alaa , Alhomoud Samar , Al-Dayel Fouad , Al-Kuraya Khawla S. 
Published: August 2019

Abstract
Colorectal cancer (CRC) is one of the leading cause of cancer-related deaths Worldwide. In Saudi Arabia, CRC is more aggressive and presents at younger age, warranting new treatment strategies. Role of TGFβ/Smad4 signaling pathway in initiation and progression of CRC is well documented. Current study examined the role of TGFβ/Smad4 signaling pathway in a large cohort of Saudi CRC, followed by in vitro analysis to dissect the dual role of TGFβ on inducing epithelial to mesenchymal transition (EMT) and apoptosis. In this study, we investigated Smad4 alterations and their association with clinicopathological outcomes in a large cohort of CRC samples using targeted capture sequencing, Fluorescent in-situ hybridisation and immunohistochemistry. Our study demonstrated high frequency of Smad4 alterations with low expression of Smad4 protein identifying a sub-group of aggressive CRC to be an independent marker for poor prognosis. Functional studies using CRC cells show that TGFβ induces Smad4 dependent EMT followed by apoptosis. Induction of mesenchymal transcriptional factors, Snail1 and Zeb1 was essential for TGFβ-induced apoptosis. Our results indicate that KLF5 acts as an oncogene in CRC cells regardless of Smad4 expression and inhibition of KLF5 is requisite for TGFβ-induced apoptosis. Furthermore, TGFβ/Smad4 signal inhibits the transcription of KLF5 that in turn switches Sox4 from tumor promoter to suppressor. A high incidence of Smad4 alterations were found in the Saudi CRC patients. Functional study results indicate that TGFβ induces Smad4 dependent EMT followed by apoptosis in CRC cells.
Citation Format: Pratheeshkumar Poyil, Abdul K. Siraj, Divya Sasidharan Padmaja, Sandeep Kumar Parvathareddy, Rong Bu, Tariq Masoodi, Yan Kong, Saravanan Thangavel, Saeeda Omer Ahmed, Nasser Al-Sanea, Luai H. Ashari, Alaa Abduljabbar, Samar Alhomoud, Fouad Al-Dayel, Khawla S. Al-Kuraya. TGFβ induced SMAD4 dependent apoptosis proceeded by EMT in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4286.
Abstract 4288: Race specific differences in G-protein decoupling from CCR9 in prostate cancer cells contribute to the differences in docetaxel response
Authors: Kapur Neeraj , Mir Hina , Singh Shailesh 
Published: August 2019

Abstract
Current treatment approaches have failed to reduce racial disparity in treatment outcome of prostate cancer (PCa) primarily due to the race-specific difference in the biology of PCa. Therefore, identification of race-specific molecular differences is needed to address the disparity in treatment outcome. In this study, we have determined the race-specific differences in CCR9 signaling. Phospho-proteomic profile of key pro-survival molecules following CCL25 treatment in African American (AA) and European American (EA) PCa cells was determined using antibody microarray and validated by western blot analyses. Coupling and decoupling of G-protein(s) with CCR9 in response to CCL25, which determines downstream signaling of CCR9 was ascertained by immunoprecipitation assay (IPA). Cell viability and apoptosis in response to a taxane drug docetaxel (DTX), with/without CCL25 stimulation and CCR9-blockade, were examined using MTT and flow cytometry, respectively. Levels of pro-apoptotic proteins were determined by western blot analyses. Our data show differential G-protein(s) decoupling from CCR9 in AA and EA cells. CCR9-activation dissociated Gαi2/3/Gαq/ Gα13/Gβ1γ7 –proteins in AA cells compared to Gαs/Gβ2γ9 and Gα13/Gαs/G β1/β3γ7 in EA cells, respectively, contribute to different molecular mechanisms supporting cell survival in cell lines derived from two races. Race-specific G-protein signaling in PCa cells, following CCL25 stimulation, is reflected into hyper-activation of molecules involved in PI3K/Akt and MEK/Erk1/2 signaling, which are associated with PCa aggressiveness in AA cells compared to EA counterparts. Further, activation of CCR9-CCL25 axis significantly influences the therapeutic response of PCa cells against DTX, which is highly compromised in AA cells compared to EA cells following CCL25 stimulation. However, this protective effect of CCL25 was abrogated after CCR9 blockade. Inhibition of MEK/Erk1/2 axis significantly improved DTX-induced cell death in AA cells, suggesting the importance of this axis in reducing drug response. Further, stimulation with CCL25, exclusively downregulated cleaved caspase-7, 8 and Bim in response to DTX in AA cells. In all, differential decoupling of G-proteins from CCR9 controls the downstream signaling and therefore determines disparity associated with PCa outcome and offer novel race-specific therapeutic targets for PCa.
Citation Format: Neeraj Kapur, Hina Mir, Shailesh Singh. Race specific differences in G-protein decoupling from CCR9 in prostate cancer cells contribute to the differences in docetaxel response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4288.
Abstract 4292: Molecular mechanism of APIO-EE-7 suppresses cell metastasis by targeting Aurora B in osteosarcoma
Authors: Jin Guoguo , Li Jitian , Guo Zhiping , Teng Junyan , Li Xiaoling , Zhao Zhenjiang 
Published: August 2019

Abstract
Osteosarcoma is one of the most prevalent malignant bone tumors in children and adolescents and has the characteristics of early metastasis, rapid progression and poor prognosis. Although with the advancement in techniques and treatment increasing the survival rates up to 60%, the prognosis remains poor for most patients with metastatic or recurrent osteosarcoma. Identifying the molecular mechanism and developing therapeutic agents for metastasis is urgent. Aurora B kinase play a key role in mitosis and have been reported to be associated with cancer metastasis. However, the role of Aurora kinase in osteosarcoma is still unclear. In this study, we identified a novel compound, referred to as APIO-EE-7, which inhibits growth and colony formation and induces apoptosis in osteosarcoma. Using computer modeling, we found that APIO-EE-7 can interact with Aurora B at ATP-binding pocket. Treatment with APIO-EE-7 can increase EMT marker expression level of E-cadherin and decrease N-cadherin, vimentin and survivin expression. Importantly, APIO-EE-7 dramatically attenuated tumor incidence and volume in osteosarcoma metastasis mouse model. Our findings suggest that APIO-EE-7 is a potential therapeutic agent against osteosarcoma metastasis by targeting Aurora B, which provides hope for rapid clinic translation.
Citation Format: Guoguo Jin, Jitian Li, Zhiping Guo, Junyan Teng, Xiaoling Li, Zhenjiang Zhao. Molecular mechanism of APIO-EE-7 suppresses cell metastasis by targeting Aurora B in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4292.
Abstract 4293: Analyzing the redox/fyn/c-Cbl pathway in glioblastoma multiforme: A mechanistic approach
Authors: Shah Neal , Stripay Jennifer 
Published: August 2019

Abstract
Glioblastoma multiforme (GBM) is the most common aggressive tumor of the central nervous system (CNS) with 10,000 newly diagnosed cases annually, and an incidence rate of 3 in 100,000 individuals in the United States. Unfortunately, the current standard of care of radiotherapy with concomitant Temozolomide (TMZ) has not been effective in consistently controlling tumor growth, as the median age of survival for patients is 14.6 months after treatment, with inevitable recurrence beyond this time. One of the difficulties that emerge when treating GBM is tumor heterogeneity. For example, GBM cells upregulate different receptor tyrosine kinases (RTKs). Signaling through RTKs enables these cells to maintain their proliferative status to ensure their survival. The E3 ubiquitin ligase c-Cbl is a negative regulator of RTKs, and our lab has found it to be physically sequestered by ARGHEF7 (Cool-1) in GBM. We identified a combination of drugs, a c-Cbl restorative agent (CRA01) and an oxidizing agent (Tamoxifen [TMX]), that decreased c-Cbl/Cool-1 complex formation and activated c-Cbl through the Redox/Fyn/c-Cbl pathway (RFC) in GBM cells. Treatment with CRA01+TMX led to degradation of RTKs. Little is known about the RFC pathway in cancer regulation or its ability to prevent cell growth in TMZ resistant GBM cells. Here, we examine ways to regulate c-Cbl in GBM cells and seek to identify the mechanism(s) resulting in c-Cbl/Cool-1 complex formation. Furthermore, we aim to use a mouse model of TMZ resistance to determine the effects of CRA01+TMX in vivo. These results will provide important knowledge on the RFC pathway that can help properly identify patients with GBM and different cancers with c-Cbl dysregulation for whom this treatment could prove beneficial.
Citation Format: Neal Shah, Jennifer Stripay. Analyzing the redox/fyn/c-Cbl pathway in glioblastoma multiforme: A mechanistic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4293.
Abstract 4296: Identification of cancer specific protein 80 (CSP-80), a novel 80 kDa MAP1a-like protein in ovarian carcinoma cells
Authors: Fadiel Ahmed , Nair Viswam S. , Aceto Peter , Naftolin Frederick 
Published: August 2019

Abstract
Background: Although interfering with the actions of microtubule-associated proteins (MAP’s) is successful against ovarian epithelial carcinoma (OVCA), knowledge of the MAP’s in OVCA cells is lacking. We sought to identify cancer-specific MAP’s in OVCA cells.Methods: Four human OVCA cell lines, primary OVCA tissue, ascitic cells and metastases from 9 patients and normal ovarian tissue from six women were compared to control human and rat brain tissue, uterine myomas (benign tumors) and rat and human non-neural organs. Modified Western blotting using panels of anti-microtubule-associated protein monoclonal antibodies were used. An in-vitro brain and OVCA mixing and recovery experiment was carried out to assess possible degradation of MAP1a by OVCA. A paclitaxel-driven tubulin assembly assay was performed to determine whether the OVCA protein has microtubule-associated protein properties. The transcriptome of CSP-80 was sequenced using primer extension sequencing.
Results: (1) In contradistinction to the 350 kDa MAP1a present in control brain extracts, only an 80 kDa molecule with MAP1a immune-reactivity was found in OVCA cell lines and tissues. No immune-reactivity was present in the negative controls. (2)Following the mixing experiments there was no increase of CSP-80; CSP-80 is not a degradation artifact of MAP1a. (3) The paclitaxel-driven tubulin assembly assay showed that CSP-80 bound to microtubules during tubulin polymerization. (4) No CSP-80 was identified in human or rat non-malignant tissues including normal human and rat brain or normal human ovary, placenta or uterine myomas, or normal rat liver, spleen or lung. (5) cDNA sequencing shows a 2603 bp fragment at a 5’ terminal of p80 to be homologous with the analogous segment of MAP1a. (6) Further testing showed that CSP-80 was present in other reproductive and non-reproductive carcinomas. Again, no 350 kDa MAP1a was present. Studies are underway to determine whether CSP-80 is a mutated protein or the product of post-transcriptional modification.
Conclusion: CSP-80 is a novel cancer-related protein that appears to be limited to an 80 kDa sequence of the MAP1a gene, or a post-transcriptionally modified product. Since CSP-80 exhibits tubulin-binding activity, this may explain the efficacy of taxane derivatives. CSP-80 may disclose some aspects of carcinogenesis, be a valuable marker of cancer and therapeutic efficacy, and offer new avenues for cancer treatment.
Citation Format: Ahmed Fadiel, Viswam S. Nair, Peter Aceto, Frederick Naftolin. Identification of cancer specific protein 80 (CSP-80), a novel 80 kDa MAP1a-like protein in ovarian carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4296.
Abstract 4312: Multiplex parallel perturbation of Akt and MAPk signaling cascades
Authors: Wagner Andrew R. , Newby Megan , Oakleaf Kary 
Published: August 2019

Abstract
PI3K/Akt and MAPk signal transduction pathways are frequently dysregulated in human cancers. Previous work described the molecular basis of pro-survival signals mediated by Akt and MAPk. Mutation in and alteration of these pathways lead to tumorigenesis. However, signal propagation varies across cell type and precise signaling kinetics is less well characterized. The goal of this study is to profile the functional state of the PI3k/Akt and MAPk signaling circuits by coupling cell viability to antibody microarray and immunofluorescence. Simultaneous detection of Akt and MAPk signaling nodes can characterize signaling parameters that correlate to localization patterns across cell type and drug treatment conditions. To examine how signal propagation varied between cell lines, staurosporine was utilized to broadly inhibit protein kinase activity in a cervical cancer cell line, HeLa, and an osteosarcoma cell line, U2-OS, as model systems. To investigate signaling pathways, each cell line was treated and analyzed in parallel by forward phase phospho-specific antibody microarray panels and high content analysis of immunofluorescent staining. Staurosporine inhibited cell proliferation in a time and concentration dependent manner in both cell lines. U2-OS cells had a higher IC50 compared to HeLa cells indicating markedly different signaling parameters between the two models. Our observations suggest detecting cell type specific signaling kinetics can be used as a framework to predict cell sensitivity to specific inhibitors and be used to monitor drug resistance.
Note: This abstract was not presented at the meeting.
Citation Format: Andrew R. Wagner, Megan Newby, Kary Oakleaf. Multiplex parallel perturbation of Akt and MAPk signaling cascades [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4312.
Abstract 436: Prediction of aggressive disease in metastatic castration-resistant prostate cancer: The role of very small nuclear circulating tumor cells
Authors: Chen Pin-Jung , Jan Yu Jen , Teng Pai-Chi , Chen Jie-Fu , Cheng Shirley , Yao Nu , Reis-Sobreiro Mariana , Lozano Amber , Gomez Amy , Tseng Hsian-Rong , Freeman Michael , Posadas Edwin 
Published: August 2019

Abstract
Background: Circulating tumor cells (CTCs) have arisen as a contemporary noninvasive prognostic biomarker for prostate cancer (PC). Previously, a subgroup of PC CTCs, with particularly small nuclei (&lt;8.54 μm), were found to be correlated with poor prognosis and the emergence of visceral metastases (VM). This subgroup was named very-small nuclear CTCs (vsnCTCs). We proposed vsnCTCs as a biomarker of aggressive disease in metastatic castration-resistant PC (mCRPC). Previous Studies also showed that the disruption of emerin, a linker of nucleoskeleton and cytoskeleton complex proteins, increases the cancer cells' capacity of migration and invasion. We hypothesize that emerin mislocalization is potentially associated with vsnCTC formation and may be a critical step for metastasis.
Methods: 35 blood samples were obtained from PC patients who failed first-line androgen deprivation therapy (ADT) and starting 2nd line treatment with abiraterone, enzalutamide, or taxane-based chemotherapy. Using our NanoVelcro CTC assay, we captured, subclassified, and enumerated the CTCs from patient samples with high-resolution imaging. Survival analyses were performed to exam the correlation between vsnCTC presence and patients’ prognosis. Concurrently, emerin staining was performed and the distribution and expression levels of emerin were analyzed in selected vsnCTC samples.
Results: The presence of one or more vsnCTCs strongly correlated with inferior overall survival (OS), progression free survival (PFS), and time to VM (TTVM). We also observed lower emerin content in vsnCTCs compared to WBC, and more prominent emerin mislocalization in vsnCTCs compared to CTCs with larger nuclei.
Conclusion: Our study strongly demonstrated the importance of morphologic characterization of CTCs and suggested that vsnCTC is a blood-borne biomarker for prediction of aggressive disease. Additionally, emerin mislocalization in vsnCTCs could be a potential biological pathway behind this morphologic phenomenon.
Citation Format: Pin-Jung Chen, Yu Jen Jan, Pai-Chi Teng, Jie-Fu Chen, Shirley Cheng, Nu Yao, Mariana Reis-Sobreiro, Amber Lozano, Amy Gomez, Hsian-Rong Tseng, Michael Freeman, Edwin Posadas. Prediction of aggressive disease in metastatic castration-resistant prostate cancer: The role of very small nuclear circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 436.