bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4090: Akt2-specific signaling in prostate cancer maintenance.
Authors: Chin Yuet Ming Rebecca , Balk Steve , Toker Alex 
Published: August 2014

Abstract
Mutations and amplification in genes regulating the PI 3-K/Akt pathway are common in prostate cancer, with deletion or mutations of PTEN being the most frequent. This has led to major efforts in developing anti-cancer drugs targeting the Akt pathway. Although the role of Akt in tumorigenesis has been studied extensively, little is known regarding isoform-specificity, and it is largely assumed that Akt isoforms play redundant roles in regulating cancer cell survival.
In this study, we have developed a tet-on inducible system for expressing Akt1/2/3 shRNAs to determine the role of Akt isoforms in prostate cancer progression. Three-dimensional (3D) matrigel cultures are employed to better recapitulate tumors growing in vivo. Administration of doxycycline (dox) in Akt1 or Akt2 shRNA PTEN-deficient LNCaP cells at the start of culture resulted in the inhibition of spheroid formation, suggesting an important role of both Akt1 and Akt2 in the initial growth of spheroids. Conversely, when spheroids were allowed to form for 7 days, followed by dox for further 10 days, no difference was observed between Akt1-depleted and control spheroids. In contrast, silencing of Akt2 resulted in complete disintegration of spheroids. Confocal microscopy studies showed a significant induction of active caspase-3 and fragmented nuclei in Akt2-silenced cells. Moreover, whereas Akt1 is uniformly expressed, Akt2 is localized in the cytoplasm and/or on the plasma membrane. Interestingly, the differences of effect of Akt isoforms on cell survival in conventional 2D culture are considerably more modest. The exclusive requirement of Akt2 for survival is also observed in PC3 prostate cancer cells, which are also PTEN-deficient. Importantly, our preliminary data indicated that Akt2, but not Akt1 knockdown, led to tumor regression in the LnCaP xenograft model.
These results indicate that Akt2, but not Akt1, plays a critical role in prostate cancer maintenance. Current efforts are aimed at identifying novel Akt isoform-specific substrates that contribute to prostate cancer progression using a genome-wide proteomic screen. The results of these studies could point to new targets for anti-cancer therapeutics.
This work was supported by grants from NIH (A.T., CA122099; R.C., 1K99CA157945-01, T32 CA081156-09)
Citation Format: Yuet Ming Rebecca Chin, Steve Balk, Alex Toker. Akt2-specific signaling in prostate cancer maintenance. [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 4090. doi:10.1158/1538-7445.AM2013-4090
Abstract 4097: Targeting of mTOR mediated signaling pathways in papillary thyroid cancer cell.
Authors: Ahmed Maqbool , Hussain Azhar R. , Al Dayel Fouad , Uddin Shahab , Al-Kuraya Khawla S. 
Published: August 2014

Abstract
The mammalian target rapamycin (mTOR) signaling cascade is a key regulatory pathway controlling initiation of mRNA in mammalian cells. Torin2 is a potent, selective and orally available mTOR inhibitor for treatment of cancer. Dysregulation of mTOR signaling has been found in many cancers, however its role Papillary Thyroid Cancer (PTC) has not been explained. Therefore in this study, we investigated the role of mTOR and its associated molecules in PTC cell lines using MTT, flow cytometry and DNA fragmentation assays and western blotting. Our data showed that Torin2 caused a dose dependent growth inhibition in all cell lines studied. Cell cycle assay showed that the sub-G1 population in TPC-1 cell increased from 12.44% in untreated control sample to 31.50% after 200nM of Torin2 treatment and 44.08% after 400nM of Torin2 treatment for 48 hours. Similarly BCPAP cells increased from 8.47% in untreated control sample to 33.54% after 200nM of Torin2 treatment and 41.16% after 400nM of Torin2 treatment for 48 hours. Further confirmation using FITC-conjugated Annexin V and PI assay showed that apoptotic cell increased from 8.89% in untreated cells to 58.54% and 73.54% after 200nM and 400nM treatment in TPC-1 cells, and from 13.24% in control to 46.74% and 70.64% in BCPAP cells, indicating a dose dependent apoptosis induced in both cell lines. Treatment of PTC cell lines with Torin2 inactivated downstream targets of mTOR; p70S6 and 4E-BP1. Torin2 treatment of PTC cell lines also induced mitochondrial dependent apoptosis via activation and cleavage of caspase-9, and 3, and cleavage of PARP. Furthermore Torin2 positively regulated autophagy by disrupting the Beclin-1 complex, releasing Beclin-1 to induce autophagy. Our results suggest mTOR and its associated signaling pathway play a critical role in PTC tumorigenesis, therefore targeting of mTOR expression may be a viable therapeutic intervention for treatment of these cancers.
Citation Format: Maqbool Ahmed, Azhar R. Hussain, Fouad Al Dayel, Shahab Uddin, Khawla S. Al-Kuraya. Targeting of mTOR mediated signaling pathways in papillary thyroid cancer cell. [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 4097. doi:10.1158/1538-7445.AM2013-4097
Abstract 4098: CXCR4 regulation of neuroblastoma migration and differentiation.
Authors: Shan Yufei , Van Golen Cynthia M. 
Published: August 2014

Abstract
CXCR4 is a chemokine involved in the migration of numerous cell types, including hematopoietic cells, neuronal cells during differentiation, and metastatic tumor cells. CXCR4 has been implicated in the invasion of metastasis of multiple tumor types that metastasize to bone, including prostate carcinoma and breast carcinoma. However, in neuroblastoma, a pediatric tumor that frequently metastasizes to bone and causes osteolytic lesions, the role of CXCR4 has not been elucidated. Several studies have suggested multiple potential roles of CXCR4 activation and signaling in neuroblastoma progression, including proliferation, migration, and invasion. Our previous studies have shown that blocking the CXCR4 receptor using a neutralizing antibody reduces migration toward the CXCR4 ligand CXCL12. However, when CXCL12 is added to neuroblastoma cells, activating the receptor, rather than an increase in migration, neurite extension and differentiation occurs. Through subsequent studies, we have demonstrated that upon stimulation, CXCR4 interacts with the actin cytoskeleton, potentially through the adaptor protein drebrin. Furthermore, this interaction appears to be dependent upon Akt. Our current hypothesis is that at low levels of CXCL12, migration is induced; upon increased activation of the receptor, however, CXCR4 is internalized, reducing the amount of receptor on the cell surface, and the internalized receptor then interacts with actin to increase process extension. This enables the neuroblastoma cells to migrate toward favorable conditions, but once the cells have reached those conditions (such as high CXCL12 levels in bone), the cells to remain in that environment. Experiments are currently being performed to test this working hypothesis.
Citation Format: Yufei Shan, Cynthia M. Van Golen. CXCR4 regulation of neuroblastoma migration and differentiation. [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 4098. doi:10.1158/1538-7445.AM2013-4098
Abstract 4103: Ptprz gene encoding a transmembrane-type protein phosphatase is up-regulated by Sox-2 in glioma.
Authors: Yamashita Yoji , Tanuma Nobuhiro , Kumabe Toshihiro , Tominaga Teiji , Shima Hiroshi , Katakura Ryuichi 
Published: August 2014

Abstract
Ptprz is a receptor-like protein-tyrosine phosphatase (PTP) abundantly expressed in neuronal and glial cells in the central nervous system. To date, several potential substrates of Ptprz such as p190RhoGAP, ErbB4, and Git-1, have been identified. In terms of its biological functions, for example, it was shown that Ptprz regulates differentiation of glial cells, but its role(s) in gliomagenesis remains obscue.
In this study, expression of Ptprz mRNA in human glioma samples were analyzed. Ptprz mRNA was up-regulated in glioma when compared to normal brain. We found that the levels of Ptprz mRNA in specimens are correlated with those of Sox-2, a transcription factor associating with glioma stemness. Knock-down of Sox-2 by siRNA decreased Ptprz mRNA of several glioma cell-lines. ChIP analysis showed the physical association of Sox2 to the putative promoter region of Ptprz gene, suggesting that Ptprz is a direct transcriptional target of Sox-2. Up-regulation of Ptprz expression may be a part of transcriptional program elicited by Sox-2, which may contribute to glioma stemness
Citation Format: Yoji Yamashita, Nobuhiro Tanuma, Toshihiro Kumabe, Teiji Tominaga, Hiroshi Shima, Ryuichi Katakura. Ptprz gene encoding a transmembrane-type protein phosphatase is up-regulated by Sox-2 in glioma. [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 4103. doi:10.1158/1538-7445.AM2013-4103
Abstract 4105: Signaling network-based analyses of sonic hedgehog pathway components: predictions and possibilities.
Authors: Malhotra Anshu , Potts Chad R. , Fernandez-Lopez Africa , Rotenberry Rachel , Kenney Anna M. 
Published: August 2014

Abstract
A subclass of Medulloblastoma shows considerable dependence on the Sonic Hedgehog (Shh) pathway. Since cellular functions are a consequence of coordinated networks involving protein-protein interactions, it is imperative to explore different events cooperating with Shh entities in order to explore novel targets for medulloblastoma therapy. The Yes Associated Protein (YAP), a component of the Hippo pathway, has been previously established as a downstream target of the Shh pathway (Fernandez et al 2011). Several interesting gene targets featured in the networks developed by us using YAP overexpression in CGNPs. A concurrent upregulation of IGF2 and H19, both imprinted genes, was observed. Possible links between the Shh/Hippo pathways and IGF2 signaling also featured in the networks developed in the study. Important links to lipid metabolism, a process highly active in medulloblastomas and essential for the proliferation of CGNPs, were also predicted. The study includes results of signaling interactions between the Shh/Hippo pathways and entities from other relevant pathways that together play a role in medulloblastoma development and proliferation.
Citation Format: Anshu Malhotra, Chad R. Potts, Africa Fernandez-Lopez, Rachel Rotenberry, Anna M. Kenney. Signaling network-based analyses of sonic hedgehog pathway components: predictions and possibilities. [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 4105. doi:10.1158/1538-7445.AM2013-4105
Abstract 4111: SDF1/CXCR4 regulates stiffness of bone marrow stromal cell through RhoA and Rac1 GTPases pathway to support myeloma cell proliferation in multiple myeloma.
Authors: Wu Dan , Su Jing , Song Qianqian , Zhou Xiaobo 
Published: August 2014

Abstract
Abstract
As the second most prevalent hematologic malignancy, multiple myeloma (MM) remains high incurable and relapse owing to intrinsic or acquired drug resistance. Therefore, new therapeutic strategies that are active in drug resistance and target molecular processes of MM progress are attractive. MM is characterized by bone marrow infiltration of malignant plasma cells. The bone marrow microenvironment is a complex structure of various extracellular components and many cell types including haematopoietic stem cells, bone marrow stromal cells (BMSCs), immune cells, bone marrow endothelial cells, as well as osteoclasts and osteoblasts. Recently study showed the physical interaction of multiple myeloma cells with BMSCs from patients of multiple myeloma in the bone marrow milieu, provokes a positive feedback loop and results in multiple myeloma pathogenesis.
We observed the myeloma BMSCs are much stiffer and more contractile than normal BMSCs. Stiffer hydrogels support colony formation and adhension of MM better than softer hydrogels. These suggested that myeloma BMSCs provide myeloma cell-friendly microenvironments for myeloma cells via exerting biomechanical forces. In order to elucidate the molecular mechanisms leading to the change of myeloma BMSCs biochemical phenotype, we analyzed myeloma BMSCs and normal BMSCs gene expression profiles. Microarray data analysis demonstrated stromal cell derived factor-1(SDF1) was over expressed in MM
BMSCs. In vitro, 100ng/ml SDF1 significantly induced actin polymerization and polarization in MM BMSCs, but not in normal BMSCs. In order to understand how SDF1 regulate BMSCs’ contractile, we conducted reverse phase protein array (RPPA) experiment. Based on RPPA data, we determined RhoA and Rac1 GTPases played important roles in SDF1 induced stiffer of BMSCs. Western blot results also approved SDF1 increased phosphate RhoA and phosphate Rac1 expression level.
In conclusion, we characterized the pivotal role of RhoA and Rac1 GTPases in regulating BMSCs stiffness and BMSCs-MM interaction. Targeting biomechanics of BMSCs in myeloma patients, restoring to their normal state would be essential for the long term cure of myeloma, provoking RhoA and Rac1 pathway as novel MM therapy.
Citation Format: Dan Wu, Jing Su, Qianqian Song, Xiaobo Zhou. SDF1/CXCR4 regulates stiffness of bone marrow stromal cell through RhoA and Rac1 GTPases pathway to support myeloma cell proliferation in multiple myeloma. [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 4111. doi:10.1158/1538-7445.AM2013-4111
Abstract 4113: Discovery and optimization of potent SDF1α antagonist peptides.
Authors: Coronella Julia A. , Fu Yanwen , Johnson Kimberly , Zhong Jingping , Campbell Lioudmila , Chen Gang , Willhite Dorian , Rosario Joselyn Del , Bhat Abhijit , Woodnutt Gary , Levin Nancy 
Published: August 2014

Abstract
The SDF1α / CXCR4 axis contributes to cancer metastasis, proliferation, angiogenesis and resistance to standard of care drugs. Here we describe novel phage display derived peptide SDF1α antagonists. Phage displayed peptides were optimized through a multistep process that resulted in a 400-fold improvement in activity, from 6.4 uM IC50 inhibition of SDF1α -driven Calcium flux to 16 nM IC50. First, peptides were affinity matured via panning of focused phage libraries. Peptides exhibiting enhanced potency were bioconjugated to the CovX antibody scaffold IgG (CVX-2000), generating bivalent CovX-Bodies with 5-fold improved potency in SDF1α driven Calcium flux assays. N and C-terminal extension of the peptide and introduction of unnatural amino acids produced an additional 11-fold improvement in activity to 16 nM. Constructs with optimal pharmacokinetic stability were identified, and demonstrated single agent tumor inhibition in a Ramos B cell lymphoma xenograft model.
Citation Format: Julia A. Coronella, Yanwen Fu, Kimberly Johnson, Jingping Zhong, Lioudmila Campbell, Gang Chen, Dorian Willhite, Joselyn Del Rosario, Abhijit Bhat, Gary Woodnutt, Nancy Levin. Discovery and optimization of potent SDF1α antagonist peptides. [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 4113. doi:10.1158/1538-7445.AM2013-4113
Abstract 4115: PI3Kα/δ inhibition has greater efficacy compared to PI3Kδ-selective inhibition in NHL with activated NFkB pathway .
Authors: Liu Ningshu , Haike Katja , Paul Juliane , Genvresse Isabelle , Wengner Antje M. , Laurent Dirk , O'Connell Damian , Mumberg Dominik , Ziegelbauer Karl 
Published: August 2014

Abstract
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two of the most common Non-Hodgkin Lymphoma (NHL) wordwide. Although the introduction of anti-CD20 monoclonal antibodies has improved the outcome of patients with follicular lymphoma, a curative treatment or an improved treatment strategy for relapsed FL are still to be developed. DLBCL is an incurable, aggressive subtype of NHL with a high unmet medical need for effective therapeutics. Activation of the PI3K-AKT pathway by B cell receptor signaling and its role in the pathogenesis of FL and DLBCL have been highlighted in a number of studies, however, the relative importance of PI3K isoforms and effective application of PI3K inhibitors for the treatment of FL and DLBCL have not been fully addressed. To answer this question, we selected and characterized a panel of cell lines representing major subtypes (e.g. ABC and GCB) and frequent mutations (e.g. CD79, Bcl2, MyD88, CARD11, or EZH2) in FL and DLBCL. Analyzing the expression of PI3K isoforms indicated that not only PI3Kδ, an isoform known to be enriched in lymphocytes, but also PI3Kα is highly expressed in DLBCL and a subset of FL cell lines. Sensitivity profiling of the PI3Kα/δ inhibitor BAY 80-6946 (biochemical IC50=0.5 nM and 0.7 nM against PI3Kα and PI3Kδ, respectively) and the PI3Kδ-selective inhibitor CAL-101 confirmed that inhibition PI3Kα/δ is more effective than inhibition of PI3Kδ, particularly PI3Kα/δ inhibition showed a broader anti-tumor spectrum in the cell line panel. For example, unlike CAL-101, BAY 80-6946 revealed potent anti-tumor activity in NFκB activating MyD88 or CARD11 mutated DLBCL cell lines both in vitro and in vivo. Further analysis of mutation status and pathway inhibition discovered an unknown PI3K isoform-dependent crosstalk to the NFκB pathway in DLBCL. The detailed molecular mechanism and the strategy of developing PI3Kα/δ inhibitor as a single agent and rationale-based combination in FL and DLBCL will be discussed. Taken together, these findings provide further insights into the mechanism of action of BAY 80-6946 and support ongoing Phase I studies in FL and DLBCL patients (Lotze et al., J Clin Oncol 30, 2012, suppl, abstr 3019, data to be updated in the presentation).
Citation Format: Ningshu Liu, Katja Haike, Juliane Paul, Isabelle Genvresse, Antje M. Wengner, Dirk Laurent, Damian O'Connell, Dominik Mumberg, Karl Ziegelbauer. PI3Kα/δ inhibition has greater efficacy compared to PI3Kδ-selective inhibition in NHL with activated NFkB 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 4115. doi:10.1158/1538-7445.AM2013-4115
Abstract 4121: Leukemic FLT3 signals via Grb10 and elevated Grb10 expression correlates with poor prognosis in acute myeloid leukemia.
Authors: Uddin Kazi J. , Rönnstrand Lars 
Published: August 2014

Abstract
The adaptor protein Grb10 plays important roles in mitogenic signaling. However, its roles in acute myeloid leukemia (AML) are predominantly unknown. Here we describe the role of Grb10 in FLT3-ITD-mediated AML. The type III receptor tyrosine kinase, FLT3 is widely expressed in AML and approximately 30% of AML patients carry an oncogenic FLT3-internal tandem duplication (ITD) mutation. We observed that Grb10 physically associates with normal and oncogenic FLT3 through FLT3 phospho-tyrosine 572 and 793 residues. Although Grb10 expression did not affect FLT3 activation or stability, its expression enhanced FLT3-mediated Akt and STAT5 phosphorylation without affecting Erk or p38 phosphorylation. Selective Grb10 depletion reduced Akt and STAT5 phosphorylation in Ba/F3 and OCI-AML-5 cells. Grb10 regulates cell cycle by accelerating G2-M transition followed by an increased cell population in S-phase. Expression of Grb10 furthermore resulted in an increased proliferation, survival and colony formation of Ba/F3-FLT3-ITD cells. Grb10 expression was significantly increased in AML patients compared to healthy controls and was also elevated in patients carrying FLT3-ITD mutants. The elevated Grb10 expression correlated to relapse as well as to poor prognosis. In addition, Grb10 expression led to resistance to chemotherapy. These results suggest that Grb10 binds to FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells that furthermore initiates drug-resistance and poor prognosis in AML.
Citation Format: Kazi J. Uddin, Lars Rönnstrand. Leukemic FLT3 signals via Grb10 and elevated Grb10 expression correlates with poor prognosis in acute myeloid leukemia. [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 4121. doi:10.1158/1538-7445.AM2013-4121
Abstract 4125: The retinoid-induced G0S2 protein undergoes ISG15ylation and destabilization.
Authors: Lu Yun , Mustachio Lisa Maria , Chinyengetere Fadzai , Yang Wei , Ma Tian , Dong Jessica , Sekula David J. , Freemantle Sarah J. , Dmitrovsky Ethan 
Published: August 2014

Abstract
The interferon stimulated protein ISG15 was one of the first ubiquitin-like modifiers discovered. Similar to ubiquitin, ISG15 is conjugated to cellular proteins through a three-step enzymatic cascade involving an activating enzyme E1 (UBE1L), a conjugating enzyme E2 and a ligase E3. Conjugated ISG15 is removed from substrate proteins by the UBE1L-ISG15 deconjugase Usp18 (UBP43). To date, few direct target proteins of the ISG15 system were found and the biologic implications of their ISG15ylation are actively under study. We previously reported that the G0/G1 switch gene 2 (G0S2) was a direct target of all-trans-retinoic acid (RA) treatment in acute promyelocytic leukemia (APL). Prior work by others found that G0S2 was able to regulate lipolysis by inhibiting adipose triglyceride lipase (ATGL). The current study extends prior work by reporting that G0S2 was induced in APL cells by RA-treatment coordinately with UBE1L, ISG15 and the deconjugase Usp18. G0S2 was also shown to be a previously unrecognized target of ISG15ylation. G0S2 species were co-immunoprecipitated with ISG15. The functional consequence of this modification was confirmed by finding that G0S2 protein stability was directly affected by the ISG15 deconjugase Usp18. Loss of Usp18 expression by transfection of individual siRNAs into studied cells led to G0S2 protein destabilization. In contrast, engineered gain of Usp18 expression in the same cells stabilized G0S2 protein. Agents that can inhibit specific protein degradation pathways were also examined. Findings revealed that G0S2 protein was stabilized by treatment with proteasome or caspase inhibitors, but was not affected by lysosome or aggresome inhibitors. Thus, these findings indicate that G0S2 is a novel ISG15 substrate and that this modification substantially reduces G0S2 protein stability. Taken together, these results provide a mechanistic basis for cross-talk between interferon and retinoid signaling at the level of the G0S2 protein that undergoes ISG15ylation. This provides evidence for a role of lipolysis regulation in both interferon and retinoid signaling. The functional consequences of this are under study in mouse models.
Citation Format: Yun Lu, Lisa Maria Mustachio, Fadzai Chinyengetere, Wei Yang, Tian Ma, Jessica Dong, David J. Sekula, Sarah J. Freemantle, Ethan Dmitrovsky. The retinoid-induced G0S2 protein undergoes ISG15ylation and destabilization. [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 4125. doi:10.1158/1538-7445.AM2013-4125