bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2850: Role of shelterin proteins for telomere shortening in chronic lymphocytic leukemia
Authors: Ishdorj Ganchimeg , Kost Sara EF , Zang Yunli , Gibson Spencer B. , Johnston James B. 
Published: July 2016

Abstract
Telomeres are important in maintaining the integrity of the chromosomes. A series of shelterin proteins (TRF1, TRF2, RAP1, POT1a and b, TIPP1 and TIN2), are involved in the maintenance of telomeres. In chronic lymphocytic leukemia (CLL), the telomeres are shorter than in normal B cells, with very short telomeres being associated with poor survival. In the present study, we demonstrate that the leukemia cell telomere length shortens over time were CLL are followed over year, indicating that telomere shortening in these cells is an ongoing process. When CLL cell metaphases were examined by Q-FISH, telomere length shortening was found to affect all chromosomes equally. To determine whether these telomere changes were related to alterations in the shelterin complex, protein levels of the six shelterins were determined in CLL cells and normal pooled B cells. In general, apart from TIN2, the shelterin protein levels were increased in CLL cells and TRF2 levels were higher in IgVH unmutated cells than in mutated cells. TIN2 protein levels were dramatically reduced in CLL cells as compared to normal B cells and an alternative isoform of TIN2 was observed, both in IgVH mutated and unmuted cases. TIN2 targeted RT-PCR followed by sequencing revealed a deletion of the entire exon 2, totaling 105 bp. This abnormality appeared in monoclonal B-cell lymphocytosis (MBL) indicating that this was an early event. In addition, a subgroup of patients showed an increase in the spliced form of TIN2, when followed over time, suggesting that this might provide the cell with a survival advantage. A protein translated from the spliced variant RNA is expected to be deleted for 35 amino acids at the N-terminus, which is the binding site for TRF2. As TIN2 maintains telomere structure by forming a complex of TRF1 and TRF2 with the telomere, this should not occur with the splice variant. Indicating a pathological role of spliced TIN2 in CLL, TRF2 was localized in both the nuclei and cytoplasm in CLL cells compared to localization only to the nucleus in normal B cells. To confirm the function of the spliced TIN2, we have overexpressed the both full length and spliced clones of TIN2 in HEK293 cells and are presently determining the localization of TRF2 and the ability to form a TRF2/TIN2 complex. Thus, these studies demonstrate a unique splice variant of TIN2 in CLL, which potentially may influence the formation of the shelterin complex and contribute to telomere shortening in this disease.
Citation Format: Ganchimeg Ishdorj, Sara EF Kost, Yunli Zang, Spencer B. Gibson, James B. Johnston. Role of shelterin proteins for telomere shortening in chronic lymphocytic leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2850.
Abstract 2861: Validation of PERK as an oncology target: A role for the unfolded protein response in cancer
Authors: Dellamaggiore Ken , Mitchell Petia , Sun Ji-Rong , Jones Jeffrey , Muchamuel Tony , Hollenback David , Tadesse Seifu , Booker Shon , Hong Fang-Tsao , Smith Adrian , Rose Mark , Beltran Pedro , Lipford James R. 
Published: July 2016

Abstract
The Unfolded Protein Response (UPR) is a cellular stress response to stressors that induce accumulation of unfolded proteins in the endoplasmic reticulum (aka ER stress). The UPR protects cells from ER stress by increasing the capacity of the ER and attenuating bulk translation. Intense or unresolved ER stress induces apoptosis through pro-apoptotic factors like CHoP. The UPR is activated in tumors, especially those of hematological origin. PERK, a UPR sensor-kinase, is highly active in these settings and might be an attractive target in oncology.
We have generated multiple potent, selective PERK inhibitor scaffolds. Low doses of PERK inhibitor (&lt; pPERK IC50) activate the downstream pathway, whereas higher doses return the pathway to baseline, resulting in a bell-shaped activity curve for all pathway readouts. The activation phase results in robust, selective killing of tumor cells in vitro and in vivo, likely through sustained translation inhibition and CHoP induction. However, application in the clinic will be challenging due to irreversible toxicity to pancreatic islets at constant, high doses and difficulty managing human dosing through a bell curve.
Emerging data might provide a solution to these challenges. PERK IP-kinase assays demonstrate that compound binding at any dose activates PERK and this activity is retained after compound removal. Exposure modeling in vitro demonstrates that transient dosing followed by compound removal results in a conventional sigmoidal dose-response curve for viability. Intermittent dosing in vivo results in CHoP induction and tumor growth inhibition even at very high doses of PERK, consistent with PERK activation following compound clearance. These findings suggest that optimized scheduling might drive robust tumor growth inhibition with reduced risk of toxicity and facilitate a standard clinical dose escalation.
Citation Format: Ken Dellamaggiore, Petia Mitchell, Ji-Rong Sun, Jeffrey Jones, Tony Muchamuel, David Hollenback, Seifu Tadesse, Shon Booker, Fang-Tsao Hong, Adrian Smith, Mark Rose, Pedro Beltran, James R. Lipford. Validation of PERK as an oncology target: A role for the unfolded protein response in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2861.
Abstract 2876: The androgen receptor utilizes protein kinase docking sites to constitutively activate Elk1
Authors: Rosati Rayna , Patki Mugdha , Dakshnamurthy Selvakumar , Chari Venkatesh , McFall Thomas , Ratnam Manohar 
Published: July 2016

Abstract
The ETS domain transcription factor Elk1 tethers the androgen receptor (AR) to chromatin, enabling sustained activation of a set of genes critical for growth in established prostate cancer cell lines. This process does not entail the transient hyper-activation of immediate early genes typical of activation of Elk1 through phosphorylation by ERK1/2. We compared the structural requirements for the association of AR and Elk1 with that for activation of Elk1 by phosphorylation using mammalian one- and two-hybrid assays. The critical polypeptide segments were mapped by systematic deletion mutagenesis. The amino-terminal A/B domain of AR, which lacks the ligand-binding domain (LBD), was adequate for association with Elk1 and to activate Elk1-AR target genes in LNCaP prostate cancer cells. The AR A/B domain also supported hormone-independent growth of LNCaP cells reflecting the ability of overexpressed natural splice variants of AR, which also lack LBD, to support prostate tumor growth. The association of AR with Elk1 was optimal in the absence of ERK1/2 and serum response factor (SRF), which are the known binding partners of Elk1. We identified two sites on Elk1 that are critical for its association with the AR A/B domain as well as the whole AR molecule. One of those sites spans amino acid residues 307 to 330, overlapping the D box, which is one of two ERK docking sites. The other site on Elk1 mapped to amino acid residues 372 to 397, overlapping the FXFP motif, which comprises the downstream ERK docking site. The results suggest that AR utilizes ERK docking sites to associate with Elk1 and is exclusive of the interaction of Elk1 with ERK1/2 or SRF. A nuclear receptor could thus function as a transcription factor co-activator by binding at protein kinase docking sites.
Citation Format: Rayna Rosati, Mugdha Patki, Selvakumar Dakshnamurthy, Venkatesh Chari, Thomas McFall, Manohar Ratnam. The androgen receptor utilizes protein kinase docking sites to constitutively activate Elk1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2876.
Abstract 2884: Role of Kaiso in intestinal tumorigenesis
Authors: Tripathi Manish K. , Reynolds Albert B. 
Published: July 2016

Abstract
p120-catenin is a master regulator of classical cadherin stability and essential for epithelial homeostasis. p120 physically interacts with transcription factor Kaiso (ZBTB33) suggesting a direct or indirect role in transcription, but its precise function with respect to Kaiso is largely unknown. Kaiso belongs to the ZBTB family of transcription factors, most of which have important roles in development and/or cancer. Interestingly, Kaiso is strongly expressed in the intestinal crypt and abruptly downregulated as the cells move up onto the villus and terminally differentiate. Kaiso is constitutively upregulated in nascent adenomas initiated by loss of the tumor suppressor APC, suggesting a link between canonical Wnt signaling, Kaiso upregulation and intestinal tumorigenesis. Here, using ChipSeq and proteomics we describe several candidate Kaiso interactions with a group of proteins that include the tumor suppressor BRCA1, CHD2 (a chromatin remodifier) and the Ets1 oncoprotein, along with preliminary evidence for functional significance relevant to intestinal tumorigenesis.
Citation Format: Manish K. Tripathi, Albert B. Reynolds. Role of Kaiso in intestinal tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2884.
Abstract 2887: Autonomous nucleolar mechanism of colon cancer cell survival through induction of perinuclear ribosomal protein translation
Authors: Shaiken Tattym E. , Opekun Antone R. 
Published: July 2016

Abstract
Hypertrophic and irregularly shaped nucleoli are characteristic of gastroitinal cancers with poor prognosis. The role of nucleolar hypertrophy in cancer cell survival has not been studied well. By suppressing several cellular pathways we observed a common cellular response mechanism that involves acceleration of perinuclear ribosomal protein synthesis and multifocal nucleoli hypertrophy. Paradoxically, the induction of perinuclear ribosomal protein biosynthesis was observed by inhibition of protein translation, suppression of protein degradation and mitochondrial activity. Acceleration of perinuclear protein translation in combination of nuclear hypertrophy was detected not only in actively dividing cells but also in quiescent, cell cycle arrested cells, and when cytotoxic effects were manifested. Intensification of perinuclear ribosomal protein translation and nucleolar hypertrophy by Rotenone-mediated damage of mitochondria supported a century long Otto Warburg observation that most cancer cells predominantly produce energy by high rate of glycolysis. Cell fractionation permitted detection of a perinuclear wall that provides a structural basis for the perinuclear protein translation. We found that that rapid- and slow-growing colon cancer cells significantly differ by abundance of ribosomes in the perinuclear region. Therefore, the perinuclear set of protein translation is an important mechanism of cancer cell survival that rescues ribosome biogenesis and leads to the drug resistance through nuclear transformation.
Citation Format: Tattym E. Shaiken, Antone R. Opekun. Autonomous nucleolar mechanism of colon cancer cell survival through induction of perinuclear ribosomal protein translation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2887.
Abstract 2889: Loss of 4E-BP1 function promotes EMT and metastasis via translational activation of snail
Authors: Ye Qing , Cai Weijia , She Qing-Bai 
Published: July 2016

Abstract
The cap-dependent translation is frequently deregulated in a variety of cancers associated with tumor progression. However, the molecular mechanisms underlying the translational activation for cancer metastatic progression remains largely elusive. Here, we demonstrate that activation of cap-dependent translation by silencing the translational repressor 4E-BP1 causes cancer epithelial cells to undergo epithelial-mesenchymal transition (EMT), which is associated with selective upregulation of the EMT inducer snail followed by repression of E-cadherin expression and promotion of cell migration and invasion as well as metastasis. Conversely, inhibition of cap-dependent translation by a dominant active mutant 4E-BP1 effectively downregulates snail expression and inhibits cell migratory/invasive capacities and metastasis. Furthermore, dephosphorylation of 4E-BP1 by mTORC1 inhibition or directly targeting the eIF4F translation initiation also profoundly attenuates snail translation/expression and cell motility, whereas knockdown of 4E-BP1 or overexpression of snail significantly rescues the inhibitory effects. Importantly, 4E-BP1-regulated snail expression is not associated with its changes in the level of transcription or protein stability. Together, these findings reveal a novel role of 4E-BP1 in the regulation of EMT and metastasis through translational control of snail expression and activity, and suggest that targeting cap-dependent translation may provide a promising approach for blocking snail-mediated metastatic potential of cancer.
Citation Format: Qing Ye, Weijia Cai, Qing-Bai She. Loss of 4E-BP1 function promotes EMT and metastasis via translational activation of snail. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2889.
Abstract 2894: Impact of honokiol on sialylation in breast cancer cells
Authors: Thulasiraman Padmamalini , Garriga Galen 
Published: July 2016

Abstract
Metastasis is a process in which malignant cells spread form the tumor of origin and colonize at distant organs. One of the diagnostic markers of metastatic progression is the overexpression of a transmembrane protein called Mucin 1 (MUC1). High levels of MUC1 have been found in tumor tissues, including breast cancer, and have been implicated in reduced survival rate. After translation of the protein, carbohydrate groups are attached to MUC1, a process called glycosylation. The resulting glycocalyx, which serves as a protective layer on epithelial surfaces, is involved in cell-cell interactions, signaling and metastasis. Glycosylation patterns differ on MUC1 in normal breast tissue in comparison with MUC1 in breast tumors. Not only do breast tumors have simpler and fewer carbohydrate chains than MUC1 from normal breast epithelial tissue, they also have increased levels of the carbohydrate derivative, sialic acid. Altered addition of sialic acid (sialylation) has been associated with cancer transformation and metastatic progression of the disease. The enzyme, α-2,3 sialyltransferase (ST3Gal I) which adds the α-2,3-linked sialic acids to MUC1 is increased in breast tumors and has been correlated with poor prognosis. Shortening of the carbohydrates units on MUC1 in breast tumors unmasks peptides that would otherwise be covered by the carbohydrates in normal MUC1, and current studies seek to identify antibodies that would directly target MUC1 on the cancer cells and in turn prevent cancer metastasis. Plant derived natural product honokiol is being studied for its anti-tumor activities. To assess the effect of honokiol on ST3Gal I, we treated breast cancer cell lines, MDA-MB-231 and MCF-7 cells with honokiol and analyzed its effect on ST3Gal I mRNA and protein expression using RT-PCR and Western Blotting, respectively. Honokiol suppressed ST3Gal I at the mRNA and protein level in both cancer cell lines. To investigate specifically whether honokiol reduces free sialic acid, we treated mammary carcinoma cells with honokiol and using the Sialic Acid Kit, we observed reduction in sialic acid in honokiol-treated mammary carcinoma cells. Future immunoprecipitation studies are underway to investigate specifically whether honokiol suppresses sialylation of MUC1. We propose that these studies will lead to the understanding on how sialylation of MUC1 alters the cellular signaling processes involved in the transformation of breast cancer and eventually to the spread of the disease.
Citation Format: Padmamalini Thulasiraman, Galen Garriga. Impact of honokiol on sialylation in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2894.
Abstract 2923: Preclinical validation of Omomyc cell-penetrating peptides as a viable in vivo anti-Myc therapy
Authors: SOUCEK. LAURA 
Published: July 2016

Abstract
Deregulated Myc is associated with most human cancers suggesting that its inhibition would be a useful therapeutic strategy. Indeed, we have shown that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer (i.e. skin, lung, pancreatic cancer and glioma), without eliciting resistance to therapy, and causes only mild, well-tolerated and reversible side effects in normal tissues. For these studies we employed a dominant negative inhibitor of Myc, called Omomyc, which is an effective inhibitor of Myc transactivation function both in vitro and in vivo. Omomyc has so far been utilized exclusively as a transgene and served as a successful proof of principle. Here we present our current results based on the direct use of Omomyc itself as a peptide displaying unexpected and efficient cell-penetrating activity (OmomycCPP). When tested in vitro, OmomycCPP causes growth arrest and/or death of several cancer cell lines. In vivo, upon intranasal administration, it rapidly biodistributes to the lung and brain, as well as to other tissues of the animals, and - like its transgenic counterpart before - has a notable therapeutic impact on KRasG12D-driven Non-small Cell Lung Cancer (NSCLSC).
In summary, our results show that OmomycCPP represents a novel and viable pharmacological strategy to inhibit Myc in vivo, a strategy that has the potential to be translated rapidly to the clinic.
Citation Format: LAURA SOUCEK. Preclinical validation of Omomyc cell-penetrating peptides as a viable in vivo anti-Myc therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2923.
Abstract 293: EGFR inhibition generates drug-tolerant persister cells by blocking AKT activity and thus inactivating Ets-1 function
Authors: Phuchareon Janyaporn , Eisele David W. , McCormick Frank , Tetsu Osamu 
Published: July 2016

Abstract
In non-small-cell lung cancer (NSCLC)—the leading cause of cancer death worldwide—about 10-20% harbor mutations in epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK). Although treatment with EGFR tyrosine kinase inhibitors (TKIs) had shown promise, drug resistance has been the most important determinant limiting its success. Recent studies have identified the mechanisms of drug resistance to TKIs, but the origin of acquired resistant cells remains to be elucidated. We consider that they must arise from a small subset of surviving populations after EGFR inhibition. Thus, we have studied the mechanism by which the subset remains viable after EGFR inhibition, despite cell death in the vast majority. Our study demonstrates that EGFR inhibition in lung cancer cells generates a drug-tolerant subpopulation by blocking AKT activity and thus inactivating Ets-1 function. The remaining cells enter a dormant, non-dividing state because of the inhibited transactivation of Ets-1 target genes cyclins D1, D3, and E2. Moreover, Ets-1 inactivation inhibits transcription of dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated, which combines with c-Src to renew activation of the Ras/MAPK pathway, causing increased cell survival by accelerating Bim protein turnover. Conversely, inhibition of elevated ERK1/2 by the addition of a MEK inhibitor enhances programmed cell death through rewiring apoptotic signaling. These observations may explain why a small subset of quiescent cells can tolerate TKIs, and might suggest that combined treatment of TKI and MEK inhibitor could overcome drug resistance in the population.
Citation Format: Janyaporn Phuchareon, David W. Eisele, Frank McCormick, Osamu Tetsu. EGFR inhibition generates drug-tolerant persister cells by blocking AKT activity and thus inactivating Ets-1 function. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 293.
Abstract 2941: Increased expression of ABCB1/MDR1 could be associated with alectinib resistance in ALK-rearranged lung cancer cells
Authors: Tsuji Takahiro , Ozasa Hiroaki , Sakamori Yuichi , Nomizo Takashi , Yagi Yoshitaka , Nagai Hiroki , Kim Young Hak , Mishima Michiaki 
Published: July 2016

Abstract
Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, has shown promising activity in ALK-rearranged non-small cell lung cancer (NSCLC). The mechanisms of drug resistance to alectinib have been still unclear. To explore whether overexpression of ATP-binding cassette (ABC) transporters might provide a potential mechanism of alectinib resistance in lung cancer, we established alectinib-resistant cell lines from NCI-H2228 and primary ALK-rearranged cells and evaluated the expression of ABC transporters.
We established ALK-rearranged NSCLC cell lines (KTOR 1, 2, and 3) from tumor cells in pleural effusion obtained from 3 patients with alectinib naïve ALK-rearranged NSCLC. In the 2 of 3 patients, tumor cells in pleural effusion were also obtained when disease progression was observed during alectinib treatment (KTOR1-RE and KTOR2-RE). Expression profiling of ABC transporters using quantitative real-time polymerase chain reaction (qRT-PCR) revealed that the expression of ABCB1 was significantly increased in KTOR1-RE and KTOR2-RE compared with the parental cells (4.6 and 10.8 folds), but not other ABC transporters. Then, alectinib-resistant NCI-H2228 cell lines (H2228-AR) were established by exposing the parental cells to stepwise-increasing alectinib up to 5μM for 10 months. We found that the ABCB1/MDR1 expression in H2228-AR cells were significantly increased (2.09-16.6 folds) compared with the parental cells using qRT-PCR and immunoblotting. Then, we examined the alternation of alectinib cytotoxicity by inhibition of ABCB1. Knockdown of ABCB1 expression using small interfering RNA and inhibition of ABCB1 by verapamil enhanced alectinib cytotoxicity in H2228-AR cells. Next, the levels of ABCB1 expression after short-term alectinib exposure were examined in NCI-H2228 and the three alectinib naïve ALK-rearranged NSCLC primary cell lines (KTOR 1, 2, and 3). In all the four ALK-rearranged cell lines, exposure to 100 nM alectinib for 72 hours induced increased expression of ABCB1 compared with control medium.
These data suggested that increased expression of ABCB1/MDR1 might be, in part, responsible acquired resistance and sensitivity to alectinib in ALK-rearranged NSCLC cells.
Citation Format: Takahiro Tsuji, Hiroaki Ozasa, Yuichi Sakamori, Takashi Nomizo, Yoshitaka Yagi, Hiroki Nagai, Young Hak Kim, Michiaki Mishima. Increased expression of ABCB1/MDR1 could be associated with alectinib resistance in ALK-rearranged lung cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2941.