bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2011: A novel bcl-2/xL inhibitor induces tumor cell apoptosis and potentiates the activity of standard chemotherapeutics
Authors: MacIntyre Terry , Powell Francoise , Lewis Paula , Adam Ammar , Lawson Deborah , Wu Jiaquan , Larsen Nicholas , Repik Galina , Parmentier Julie , Secrist Paul , Ioaniddis Stephanos , Byth Kate 
Published: August 2012

Abstract
Tumor cells often evade apoptosis by tipping the balance of Bcl-2 family and BH3-only protein expression towards a more anti-apoptotic environment, thus providing a survival advantage as well as a means of resistance to anti-cancer therapies. Indeed, over-expression of Bcl-2 family members has been shown to confer chemo-resistance in multiple tumor types. One potential result of this survival adaptation, however, is that the tumor cells become dependent on said Bcl-2 family member and hence increasingly vulnerable to targeted pro-apoptotic BH3 mimetics. Clinical validation of this concept has been demonstrated with the Bcl-2/xL inhibitor Navitoclax, where as a single agent in phase I/II trials in relapsed, refractory CLL patients, a 20% response rate was observed. Due to the potential that directly targeting the apoptotic machinery holds in treating cancer, developing BH3 mimetics that easily and effectively combine with standard chemotherapies is an attractive proposition. With this in mind, we have discovered and characterized a novel small molecule BH3 mimetic with nanomolar affinity for Bcl-2 and Bcl-xL. Here we characterize the in vitro and in vivo activity of this inhibitor in a variety of cell types. In addition to exhibiting potent single agent anti-cancer activity, it also potentiates the effectiveness of standard chemotherapeutic agents. Importantly, it also induces regression of sensitive tumors in vivo after a single IV bolus dose. Overall, this novel Bcl-2/xL inhibitor represents an exciting tool to further explore the mechanistic rationale for using potent BH3 mimetics as a foundation therapy across a broad range of tumor types where resistance to standard therapies arises from deregulation of the Bcl-2 family of anti-apoptotic proteins.
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 2011. doi:1538-7445.AM2012-2011
Abstract 2014: IRF8 regulates Bax transcription in primary myeloid cells differentiation and pathogenesis in CML
Authors: Hu Xiaolin , Yang Jine , Liu Kebin 
Published: August 2012

Abstract
Chronic myelogeneous leukemia (CML) is a myeloid proliferative disease featured in a chronic stage of clonal expansion of undifferentiated myeloid cells followed by an accelerated stage with uncontrolled clonal expansion of blastocytes that quickly progresses to blast crisis. IFN regulatory factor 8 (IRF8) is a key transcription factor for myeloid cell differentiation and its expression is frequently lost in hematopoietic cells of human myeloid leukemia patients. IRF8-deficient mice exhibit similar symptoms to human CML patients with accumulation of undifferentiated myeloid cells in the bone marrow and periphery blood that can progress to a fatal blast crisis, thus IRF8 is a myeloid leukemia suppressor. Although the role of IRF8 function in CML has highly appreciated, the molecular mechanisms underlying IRF8 function in CML are still largely unknown. In this study, we use IRF8 knockout mice as proof of study. We observed that Bax expression level is low in bone marrow progenitor cells and increases dramatically in primary myeloid cells in wt mice. In contrast, Bax expression level remained at a low level in primary myeloid cells in IRF8 KO mice. However, in vitro IRF8 KO bone marrow-differentiated myeloid cells expressed Bax at a level as high as that in wild type myeloid cells. Furthermore, we demonstrated that IRF8 specifically binds to the Bax promoter region in primary myeloid cells. Functional analysis showed that IRF8 deficiency results in increased resistance of the primary myeloid cells to Fas-mediated apoptosis, which indicates that CML cells could use the strategy of silencing IRF8 to downregulate pro-apoptotic gene Bax to acquire apoptosis resistance. To summarize, our findings show that IRF8 directly regulates Bax transcription in vivo, but not in vitro during myeloid cell lineage differentiation and silencing IRF8 to disrupt apoptosis related genes expression could result in uncontrolled clonal expansion of myeloid cells and leukemia development.
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 2014. doi:1538-7445.AM2012-2014
Abstract 2015: Lysophosphatidylcholine induces apoptosis via suppressing STAT3 and HDAC3 activities and binding to the Bcl-xL promoter in K562 chronic myelogenous leukemia cells
Authors: hoon Jung Ji , Jeong Soo-Jin , Kim Ji-Hyun , Lee Hyo-Jung , Lee Hyo-Jeong , Lee Eun-Ok , Kim Junghyo , Kim Sung-Hoon 
Published: August 2012

Abstract
Lysophosphatidylcholine (LPC) is a class of chemical compound which are derived from phosphatidylcholines usually isolated from the surface of wheat starch granules. In the present study, we investigated the molecular mechanisms responsible for LPC-induced apoptosis in chronic myeloid leukemia K562 cells. LPC exerted the inhibitory effect on the viability of K562 cells as well as other leukemic cell lines HL-60 and U937. Nonetheless, LPC significantly increased the acetylation of histone H3 at K18, 9 and 23 in K562 cells, but not in HL-60 and U937 cells. Consistently, LPC reduced histone deacetylase (HDAC) transcriptional activity and the expression of HDAC3 at protein level. LPC suppressed phosphorylation of mTOR and AKT, the upstream kinases of HDACs and induced p27 expression. We also found that LPC mediated inactivation of signal transducer and activator of transcription 3 (STAT3)-related signaling pathway in K562 cells, but not HL-60 and U937. LPC significantly inhibited phosphorylation and the DNA binding activity of STAT3, phosphorylation of Src and Janus activated kinase 2 (JAK2) as well as the expression of STAT3 target genes Cyclin D1, Cyclin E, Bcl-xL, Bcl-2, and Survivin at both protein and mRNA levels. LPC stimulated protein tyrosin phosphatases Src homology 2 domain-containing phosphatase 1 (SHP-1), but not SHP-2, SOCS-1 and PTEN. Blocking SHP-1 using sodium pervanadate or SHP-1 specific siRNA reversed LPC-mediated inactivation of STAT3 and HDAC and induction of apoptosis. Of importance, LPC blocked the nuclear translocation and interaction of HDAC3 and STAT3 as well as their binding onto the Bcl-xL promoter. Overall, our findings demonstrate that LPC has a potent anti-cancer activity through inducing apoptosis by suppressing HDAC3/STAT3 activation and binding to the Bcl-xL promoter in K562 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 2015. doi:1538-7445.AM2012-2015
Abstract 2020: Suppression of Twist expression sensitizes human non-small cell lung cancer (NSCLC) cells to cisplatin
Authors: Park In-Chul 
Published: August 2012

Abstract
Twist, a highly conserved basic helix-loop-helix transcriptional factor, is a major inducer of epithelial-mesenchymal transition (EMT) and involved in different phases of tumorigenicity. The elevated Twist expression in cancer cells has been shown to promote metastasis and induce chemoresistance. In this study, we have investigated the mechanism of action by which Twist depletion induces chemosensitivity of lung cancer cells to chemotherapeutic agent. We found that knock-down of Twist expression by siRNAs sensitized H1299 cells to cisplatin by inhibiting mTOR activity. Inhibition of mTOR pathway using mTOR or S6K siRNAs led to potentiate cell death in cisplatin resistant H1299 cells. Our results suggest that suppression of Twist expression sensitized NSCLC cells to cisplatin treatment by down-regulating mTOR pathway.
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 2020. doi:1538-7445.AM2012-2020
Abstract 2026: Targeted delivery of therapeutic NefM1 peptide with single-walled carbon nanotubes (SWNTs) suppresses growth of 3-D cultures of breast and colon cancers
Authors: Janagama Dasharatham G. , Basson Marc D. , Bumpers Harvey L. 
Published: August 2012

Abstract
Background and Objectives: In vitro studies with NefM1 peptide demonstrated apoptotic effects on a number of cancer cell lines containing CXCR4 receptors. This suggests that NefM1 apoptotic peptides can be used as a therapeutic agent for breast and colon cancers. In this study we hypothesized these cancers cultured as 3-D tumor spheres will undergo greater regression and destruction after treatment with NefM1 peptide- linked-carbon nanotubes (SWNTs) particles than with NefM1 peptide alone. Material and Methods: Human breast cancer (MDA-MB-231, MDA-MB-468) and colon cancer (HT-29, WiDr, SW 480) cells were cultured with 1% Sea Prep hydrogel in supplemented RPMI1640 medium. After 3 weeks the 3-D cultures developed as tumor spheres. Like in vivo conditions these 3-D cultures had cell-cell interactions and the sphere is held together by an extracellular matrix. The cultures were treated with NefM1 peptide and NefM1 carbon nanotubes (SWNTs) to compare their relative effects on the growth of the tumor spheres. The viability status of the tumor spheres was established using ethidium bromide and acridine stain and fluorescent microscopy. The Nef peptide was linked to SWNTs using thionine and binding was verified by gel electrophoresis. Transmission electron microscopy (TEM) showed internalization of NefM1-SWNTs nanoparticles. Results: In 3-D cultures, the SeaPrep hydrogel facilitated the growth of tumor spheres. All breast (MDA-MB-231, MDA-MB-468) and colon (HT-29, WiDr, SW-480) tumor spheres showed reduction and disintegration with nefM1 administration. This was enhanced with the NefM1- SWNTs conjugate which destroyed all cells in the culture. This indicated effective delivery of NefM1 into the cells via SWNTs. This is novel in that not only were these growing tumor spheres killed by the peptide binding to the CXCR-4 receptors, but the nanoparticles allowed for increased internalization of the peptide into the cells. The NefM1-SWNT's will undergo further study regarding its ability to enhance suppression of these tumors in SCID mice models. Conclusion: An apoptotic peptide (NefM1) can be linked to a nanoparticle which enhances its cytotoxicity to breast and colorectal cancers in vitro. Using 3-D cultured tumor spheres to evaluate the suppression of cancer growth is convenient and cost effective for drug delivery and drug discovery.
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 2026. doi:1538-7445.AM2012-2026
Abstract 2029: Rictor regulates FBXW7-dependent c-Myc and cyclin E degradation in colorectal cancer
Authors: Guo Zheng , Zhou Yuning , Evers Mark , Wang Qingding 
Published: August 2012

Abstract
Rictor (Rapamycin-insensitive companion of mTOR) forms a complex with mTOR and phosphorylates and activates Akt. Activation of Akt induces expression of c-Myc and cyclin E, which are overexpressed in colorectal cancer and play an important role in colorectal cancer cell proliferation. Here, we show that rictor associates with FBXW7 to form an E3 complex participating in the regulation of c-Myc and cyclin E degradation. The Rictor-FBXW7 complex is biochemically distinct from the previously reported mTORC2 and can be immunoprecipitated independently of mTORC2. Moreover, disruption of the interaction between rictor and FBXW7 by knockdown of rictor increased FBXW7 ubiquitination and degradation. Knocking down of rictor in serum-deprived colorectal cancer cells results in the decreased ubiquitination and increased protein levels of c-Myc and cyclin E while overexpression of rictor induces the degradation of c-Myc and cyclin E proteins. Genetic knockout of FBXW7 blunts the effects of rictor, suggesting that rictor regulation of c-Myc and cyclin E requires FBXW7. Our findings identify rictor as an important component of FBXW7 E3 ligase complex participating in the regulation of c-Myc and cyclin E protein ubiquitination and degradation. Importantly, our results suggest that elevated growth factor signaling may contribute to decrease Rictor/FBXW7-mediated ubiquitination of c-Myc and cyclin E, thus leading to accumulation of cyclin E and c-Myc in colorectal 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 2029. doi:1538-7445.AM2012-2029
Abstract 2030: Mechanisms of E2F-mediated centrosome amplification in HER2 positive breast cancer
Authors: Lee Miyoung , Saavedra Harold I. 
Published: August 2012

Abstract
Centrosome amplification associates with most human cancers and has been suggested to trigger tumor initiation and progression. Centrosomes are the major microtubule organizing centers in animal cells. They are duplicated once in each cell cycle and duplicated centrosomes establish mitotic spindle bipolarity. Centrosome duplication is tightly regulated because deregulated centrosome duplication leads to centrosome amplification, multipolar and pseudobipolar mitotic spindles that potentiate chromosome instability and may trigger tumorigenesis. One of the tumor types in which the relationship between centrosome amplification and tumorigenesis is well known are breast cancers, as most breast tumors exhibit centrosome amplification. Centrosome amplification arises through various mechanisms, such as deregulation of cell cycle regulators, oncogenes and tumor suppressor genes. Our laboratory discovered that HER2 positive breast cancer cells and K-RasG12D pre-malignant mouse mammary lesions displayed overexpressed E2F1-3 transcriptional activators. Although E2Fs are involved in various cellular processes, including the regulation of the cell and centrosome duplication cycles and differentiation, the role of E2Fs in centrosome amplification in breast tumors is unknown. To study the role of the E2F activators in centrosome amplification, we first assayed centrosome amplification in the E2F-overexpressing HER2 positive breast cancer cells, HCC1954, JIMT1 and SKBR3. There was increased centrosome amplification in the HER2 positive cell lines HCC1954, JIMT1 or SKBR3 relative to MCF10A control mammary epithelial cells. To find if centrosome amplification shown in HER2 positive cells overexpressing E2F1-3 was E2F-specific, the siRNA-mediated silencing technique was applied to transiently knock-down the E2F activators (E2F1-3a) and cells were assayed for centrosome amplification. In addition, to permanently knockdown E2Fs in HER2 positive cells, shRNA-mediated silencing technique will be applied. Western blots confirmed that E2Fs knockdown was efficient, followed by decreased centrosome amplification in HER2 positive cells downregulated for E2F1 and E2F3a; results for E2F2 are still awaiting. These data suggested that centrosome amplification detected in HER2 positive cells is specific to the E2F activators. Future experiments will involve the identification of E2F-dependent transcriptional targets mediating centrosome amplification in HER2 positive 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 2030. doi:1538-7445.AM2012-2030
Abstract 2033: Protection of quiescent fibroblasts from proteasome inhibition-mediated proteotoxicity
Authors: Legesse-Miller Aster , Raitman Irene , Haley Erin M. , Liao Albert , Sun Lova L. , Wang David J. , Lemons Johanna M.S. , Suh Eric J. , Johnson Elizabeth L. , Laund Benjamin A. , Coller Hilary A. 
Published: August 2012

Abstract
Objectives: The aim of this study is to investigate quiescence-related resistance to proteasome-inhibition mediated proteotoxicity, and its regulatory mechanisms. Introduction: Quiescence, the reversible arrest of cellular proliferation, is critical for normal cellular development and tissue maintenance. Moreover, while proteasome inhibitors (PIs) are used to treat specific cancers, it has been shown that subsets of cells within a tumor, through quiescence, avoid PI-induced apoptosis and survive. Thus, deciphering the mechanisms through which quiescent cells resist proteasome inhibition is of basic and clinical relevance. Methods: Proliferating and quiescent primary human fibroblasts were used as a model system to study the effects of PIs (MG132, epoxomycin and Bortezomib). Flow cytometry, Western blots, microscopy and microarrays were used to identify specific pathways activated by proliferating and quiescent fibroblasts in response to proteasome inhibition. Results: We found that the proteasome-inhibited quiescent fibroblasts maintain viability while proliferating fibroblasts rapidly undergo apoptosis. We further found that proteasome-inhibited proliferating and quiescent fibroblasts up-regulate multiple protective pathways, including authophagy, chaperones and antioxidants, and evidence no observable difference in proteasome-mediated degradation pathway activity. However, we found that in proliferating fibroblasts, proteasome inhibition leads to increased reactive oxygen species (ROS), peri-nuclear protein aggresomes, and apoptotic cell death. By comparison, proteasome-inhibited quiescent cells display selective up-regulation of MnSOD (a ROS detoxifying enzyme), dispersed protein aggregates, and less apoptotic cell death. Knockdown of p62/SQSTM1 (a protein important for aggresome formation) or treatment with an antioxidant N-acetylcysteine results in reduced aggresome formation and decreased apoptosis in response to proteasome inhibition. Moreover, inhibition of autophagy sensitizes serum-starved quiescent cells to proteasome inhibition induced apoptosis. This suggests that multiple mechanisms, including autophagy, ROS detoxification and differential subcellular trafficking of ubiquitinated proteins are implicated in quiescence-related resistance to PI-induced apoptosis. These results point to possible strategies for improving the effectiveness of PIs in cancer treatment.
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 2033. doi:1538-7445.AM2012-2033
Abstract 2034: The Fbw7 tumor suppressor: Genetic and biochemical approaches to study a dimeric ubiquitin ligase
Authors: Larimore Elizabeth A. , Welcker Markus , Clurman Bruce E. 
Published: August 2012

Abstract
Fbw7, the human ortholog of yeast Cdc4, is the substrate-recognition component of a cullin-RING ubiquitin ligase and regulates a number of oncoprotein substrates including cyclin E, c-Myc, Notch, and c-Jun. A growing number of additional pro-growth and pro-survival factors have been more recently described as Fbw7 targets. Accordingly, Fbw7 is a tumor suppressor and is mutated in approximately ten percent of human malignancies. Its loss leads to chromosomal instability and tumorigenesis. Fbw7 binds its substrates after they become phosphorylated within a consensus sequence called a Cdc4 phospho-degron (CPD). CPD phosphorylation creates a high-affinity binding site for Fbw7, which brings the ligase machinery into proximity with the substrate, leading to ubiquitylation and proteasomal degradation of the substrate. Interestingly, Fbw7 contains a conserved dimerization domain and we can show the protein primarily forms dimers in cells. One Fbw7 dimer contains two substrate-binding interfaces and may make two independent CPD contacts, but the physiologic function of Fbw7 dimerization is still elusive. Using gene-targeting, we studied the effects of ablating Fbw7 dimerization in vivo and found endogenous cyclin E and c-Myc regulation are moderately affected. Using purified Fbw7 monomers or dimers in in vitro ubiquitylation assays, we observed that a dimeric ligase is able to conjugate ubiquitin moieties onto a wider variety of substrate lysine residues than can the monomeric ligase. This is likely due to the greater spatial reach of the dimer. Additionally, preliminary data shows that the dimer may be capable of catalyzing the formation of non-K48-linked polyubiquitin chains, whereas the monomer is not. Cancer-associated mutations in Fbw7 most often target three arginine residues that form a pocket for binding phosphorylated substrate CPDs. Mutation of any of these arginines render Fbw7 unable to bind substrates and properly regulate their abundance. However, these mutations occur typically in only one allele. Dimerization of Fbw7 may explain why such heterozygous mutations are sufficient for tumorigenesis: the mutant form may dominantly inhibit enzyme function of the wild-type allele through dimerization. We have generated hetero-typic Fbw7 dimers containing one wild-type and one mutant protein in each dimer and are currently studying its binding and ubiquitylation capabilities. Given the importance of Fbw7 and its substrates in tumor-progression pathways, the results of this study will further our understanding of human tumor suppression.
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 2034. doi:1538-7445.AM2012-2034