bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2056: Evidence against hypoxic-dependent activation of carbonic anhydrase IX in MDA-MB-231 breast cancer cells
Authors: Frost Susan C. , Li Ying , Tu Chingkuang , Silverman David N. 
Published: July 2012

Abstract
Carbonic anhydrase IX (CAIX) is a membrane-bound, tumor-related enzyme the expression of which is often considered a marker for hypoxia, an indicator of poor prognosis, and associated with acidification of the tumor microenvironment. Many studies have shown that CAIX expression is induced by hypoxia exposing its catalytic domain to the interstitial milieu. Several recent studies have suggested that hypoxic conditions may also permit activation of CAIX, perhaps by causing a conformational change which exposes the catalytic pocket. Our goal was to assess the effect of anoxic conditions on CAIX activity in MDA-MB-231 cells, previously exposed to hypoxia which increases CAIX expression in the absence of other membrane-bound carbonic anhydrase (CA) family members.
We have taken advantage of membrane inlet mass spectrometry (MIMS) to directly analyze CA activity in intact cells by measuring the 18O exchange between CO2 and H2O. This method distinguishes between intracellular and extracellular CA activity. MDA-MB-231 cells were exposed to 1% oxygen for 16 hours after which they were isolated under normoxic or anoxic conditions. CA activity was then measured, again under normoxic or anoxic conditions. These data show biphasic depletion of 18O from CO2 under both normoxic and anoxic assay conditions. The first phase (which occurs over the first 20-40 seconds) represents a rapid diffusion of CO2 into cells where it is exposed to intracellular CAII. A catalytic cycle depletes 18O followed by efflux of CO2 from the cell. There was no difference in this phase between cells prepared and assayed under normoxic or anoxic conditions. The second phase (from 200-500 sec) is dominated by the hydration-dehydration reaction of CO2/HCO3− catalyzed by exofacial CA activity (CAIX). In cells exposed to anoxia, the slope of the second phase was greater than that observed with cells exposed to normoxic conditions indicating elevated CAIX activity. While this provided evidence that oxygen limitation might influence CAIX activity, the Ki values for two impermeant CA inhibitors, Cpd 5C and a polymeric sulfonamide, did not differ between anoxic and normoxic cells. We conclude from these data that the catalytic site of CAIX is exposed and functional under both anoxic or normoxic conditions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2056. doi:10.1158/1538-7445.AM2011-2056
Abstract 2070: XBP-1 promotes cell survival by activating the unfolded protein response (UPR) in antiestrogen resistance in breast cancer
Authors: Shajahan Ayesha N. , Hickman F. Edward , Cook Katherine , Clarke Robert 
Published: July 2012

Abstract
Most of the 192,000 newly diagnosed cases of invasive breast cancer in 2011 will be estrogen receptor positive alpha positive (ER+). Endocrine therapy, administered as an antiestrogen, e.g., Tamoxifen (TAM) or Faslodex (Fulvestrant; ICI 182,780) or an aromatase inhibitor (AI), e.g., Letrozole (LET), is the least toxic and most effective means to manage the hormone-dependent breast cancer in such patients. However, resistance to endocrine therapy remains a significant clinical problem. Our group has shown that antiestrogen resistant breast cancer cells over-express X-Box Binding Protein 1 (XBP1), a transcription factor that belongs to the basic region/leucine zipper (bZIP) family. XBP1(U) and XBP1(S) variants result from an unconventional splicing of the XBP1 mRNA by IRE1alpha. In the unfolded protein response (UPR), endoplasmic reticulum proteins (IRE1alpha, ATF6 and PERK) sense cellular stress to regulate the accumulation of unfolded proteins. Initially a compensatory mechanism allowing cells to recover normal endoplasmic reticulum function, prolonged UPR may induce cell death; this is often dependent upon which arm of the UPR predominates. XBP1 is an obligate component in both the IRE1alpha and ATF6 arms of the UPR. Our study shows that antiestrogen resistant breast cancer cells survive by activating pro-survival autophagy through XBP1-mediated UPR. MCF7/LCC9 [Faslodex resistant; TAM cross-resistant; high level of XBP1(S)] cells showed an increase in UPR signaling as detected by increased expression of BiP/GRP78. Antiestrogen-sensitive cells that over-express XBP1(S) show decreased sensitivity to Faslodex and show increased levels of basal and Faslodex-induced autophagy as measured by cleaved LC3BII protein fragment, GFP-LC3 activity, and reduced expression of p62/SQSTM1. Thus, we conclude that antiestrogen resistant breast cancer cells evade cell death by activating the XBP1-regulated arms of the UPR that results in prosurvival autophagy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2070. doi:10.1158/1538-7445.AM2011-2070
Abstract 2075: miRs are altered by caloric restriction: Therapeutic implications
Authors: Saleh Anthony , Savage Jason E. , Harris Curtis C. , Mitchell James B. , Simone Nicole L. 
Published: July 2012

Abstract
The anti-cancer effect of caloric restriction (CR) is thought to involve repression of insulin/IGF-1 signaling, which activates PI3k/AKT, a pro-proliferation pathway that is often up regulated in tumor cells. Several microRNAs have been shown to play roles in tumor suppression and oncogenesis. In this study we sought to determine what if any microRNAs can play a role in the anticancer effects of caloric restriction. To determine this we performed microRNA arrays on total RNA from ad libitum fed, CR, or 24-hour fasted C57b/J mice. We assessed liver and brain tissues since these are known to have great alterations with caloric restriction and we also assessed breast tissue for which there is little data with dietary alteration. Our results show that both caloric restriction and fasting alters the expression of several cancer relevant microRNAs all of the tissues analyzed. A reduction of the miR-200 and mir-17-92 cluster of miRNAs was noted and these miR's are known to be upregulated in many cancers. Conversely, increases in the mir-29 and mir-30 families of miRNAs were noted which are noted to be downregulated in many cancers. mir-29 is known to target p85 protein of PI3K which would also reduce AKT signaling. In addition, mir-29 and mir-30 are predicted to target IGF-1 and IGF-1R respectively. Analyses of protein and mRNA levels confirm that IGF-1 and IGF-1 R are down regulated by CR and fasting. Cell culture studies are ongoing to show direct targeting of these transcripts by mir-29 and mir-30. This study shows that microRNAs are involved in the potential benefits of caloric restriction and show a general role for regulation of insulin related signaling by mir-29 and mir-30 which may be provide a target that can be exploited for therapeutic benefit.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2075. doi:10.1158/1538-7445.AM2011-2075
Abstract 2085: Reactive oxygen species promote signaling in neuroblastoma cells
Authors: Harrison Dominick , Joanis Ruth , van Golen Cynthia M. 
Published: July 2012

Abstract
Neuroblastoma is a rare cancer of the sympathetic nervous system that is commonly diagnosed in children before the age of five. Neuroblastoma affects 1 out of 100,000 children and about 700 new cases of neuroblastoma each year. Most cases of neuroblastoma begin in the abdomen in the adrenal gland, or next to spinal cord and in the chest. Neuroblastoma is known to spread to the bones, face, skull, pelvis, shoulder, arms, legs, bone marrow, liver, lymph nodes, skin and around the eyes. Currently, there is no explanation for the cause of neuroblastoma. Our lab seeks to understand the mechanisms used for these cells to metastasize. The Erk pathway, part of the mitogen activated protein kinases, helps to regulate the cell cycle, proliferation, invasion and metastasis. The PI3k/Akt pathway regulates cell growth, survival, and activation of transcription factors such as hypoxia inducible factors (HIFs). Hypoxia is a state where the cell is experiencing a lower than normal oxygen tension activating HIF-1 alpha and HIF-2 to cause an expression of target genes for angiogenesis, (generation of new blood cells), erythropoiesis (formation of new blood cells), and glucose transport into cells enabling them to survive under hypoxic conditions and acquire access to an oxygen supply. Hypoxia increases reactive oxygen species used to stabilize HIF-1 alpha. Reactive oxygen species generation is dependent on oxygen induced changes in the redox state of the electron transport chain. Low levels of reactive oxygen species can regulate controlled proliferation. However, high levels of reactive oxygen species lead to DNA damage and genomic instability by activating these signaling pathways stopping cell death in senescence leading to uncontrolled proliferation. Therefore, our hypothesis is that low levels of reactive oxygen species promote neuroblastoma cell survival through upregulation of survival signaling, whereas high levels of reactive oxygen species induce neuroblastoma cell apoptosis. To test this idea, we exposed an aggressive, metastatic cell lines, IMR 32 neuroblastoma cells, to increasing concentrations of hydrogen peroxide, used to induce reactive oxygen species formation. Cells were analyzed morphologically for apoptosis. With increasing concentrations of hydrogen peroxide, IMR32 neuroblastoma cells round up and become less adherent. High doses of hydrogen peroxide induce cell fragmentation indicative of apoptosis. We are currently investigating the effect of hydrogen peroxide on the induction of caspase-3, a proapoptotic molecule, and DNA fragmentation, measured by TUNEL assay. Our data suggest that reactive oxygen species induce apoptosis in human neuroblastoma cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2085. doi:10.1158/1538-7445.AM2011-2085
Abstract 2095: Tunicamycin inhibits triple negative breast cancer progression
Authors: Banerjee Aditi , Duran Elizabeth , Couto Javier A. , Zhang Zhenbo , Espinoza Lydia A. , Banerjee Sushanta K. , Baksi Krishna , Banerjee Dipak K. 
Published: July 2012

Abstract
Triple negative (ER−/PR−/EGFR−) breast cancer accounts for 15% of all breast cancers. A large percentage of them are African and African-American women who are premenopausal. Histologically, the cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers. Because of the absence of specific treatment guidelines, these patients are managed with standard treatment which leaves them associated with a high rate of local and systemic relapse. Angiogenesis is crucial for breast tumor growth and progression. Our laboratory has recently established that Tunicamycin (TM; an antibiotic and a glucosamine-containing pyrimidine nucleoside) interferes with the dynamic relationship between asparagine-linked (N-linked) glycosylation and angiogenesis. As a result, the xenograft developed in athymic nude mice [Balb/c (nu/nu)] with human breast cancer cell line MDA-MB-231 is reduced ∼65% in one week when Tunicamycin was given orally (0.25 mg/Kg) twice per week. To understand if it is due to a direct effect of Tunicamycin on the tumor microvsculature or a nutritional deprivation of the tumor cells due to insufficient blood flow, we have studied the effect of Tunicamycin on MDA-MB-231 breast cancer cells. When titrated with Tunicamycin (0.1 µg/ml, 1.0 µg/ml and 10.0 µg/ml) for seven days, the cell growth was inhibited almost quantitatively at all concentrations and as a function of time. In addition, no colony was formed at 1 µg/ml of Tunicamycin, the concentration used in all our experiments. Protein expression by western blotting and the gene expression by qRT-PCR indicated down-regulation of cyclin D1, and up-regulation of wild type p53, phopspho p53(ser 392), Bcl-2 and caspase-3 with no changes in the cdk-4 expression. These results strongly supported cell cycle arrest in G1 followed by the induction of apoptosis. Our recent study has demonstrated that Tunicamycin induces ER stress and consequently the apoptosis by unfolded protein response (upr) in breast tumor microvasculature. When examined, the MDA-MB-231 cells expressed high levels of GRP-78 as well as phospho PERK, a translational attenuator. Thus, we conclude that the MDA-MB-231 breast cancer cells experienced upr-mediated apoptotic death in the presence of Tunicamycin and strongly supported Tunicamycin's potential for a glycotherapeutic for treating a triple negative breast cancer in the clinic. Supported in part by grants from Susan G. Komen for the Cure (BCTR06582) and NIH/NCRR/RCMI G12-RR03035 (KB).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2095. doi:10.1158/1538-7445.AM2011-2095
Abstract 2096: Estrogen receptor alpha activation mediates a novel mitochondrial unfolded protein response
Authors: Papa Luena , Germain Doris 
Published: July 2012

Abstract
Unfolded protein responses (UPR) of the endoplasmic-reticulum and of the matrix of the mitochondria have been described. Our data indicates that accumulation of proteins in the inter-membrane space of the mitochondria (IMS) activates a distinct UPR from that induced by stress in the mitochondrial matrix. We show that upon IMS-stress, cells activate the Estrogen Receptor (ERα) in a ligand independent fashion through ROS overproduction and AKT phosphorylation. ERα activation further triggers the induction of the mitochondrial regulator NRF-1 and the IMS protease Omi. In addition, IMS stress leads to an acceleration in the trypsin-like activity of the proteasome. Since we reported a proteasome and Omi-dependent checkpoint that limits the import of IMS proteins, these results suggest that this novel UPR acts as cyto-protective responses to overcome IMS-stress. Indeed, we show that whereas ERα is required for activation of these cyto-protective responses, its ligand-independent activation is necessary to prevent IMS stress-induced collapse in the mitochondrial potential. Notably, our result show that upon mitochondrial dysfunction, cells trigger the retrograde pathway involving the activation of ERα to facilitate the recovery of the physiological functions of the mitochondria and maintain their integrity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2096. doi:10.1158/1538-7445.AM2011-2096
Abstract 2103: Reduced Tip60 expression as a predictive biomarker for advanced melanoma and patient outcome
Authors: Chen Guangdi , Chen Yabin , Zhang Zhizhong , Martinka Magdalena , Li Gang 
Published: July 2012

Abstract
The tumor suppressor Tip60 plays a major role in transcription, DNA damage response, apoptosis and cancer development. We investigated the role of Tip60 in melanoma pathogenesis and assessed the prognostic value of Tip60 expression on melanoma patient survival. Two sets of tissue microarrays were constructed consisting of 448 cases of melanomas (201 for the training set and 247 for the validation set) and 105 cases of nevi. The TMA was assessed for Tip60 expression by immunohistochemistry. The Kaplan-Meier method was used to evaluate the patient survival, and univariate and multivariate Cox regression models were performed to estimate the harzard ratios (HR) at five-year follow-up. We found that Tip60 expression was significantly reduced in metastatic melanoma compared to normal nevi (P = 0.045), dysplastic nevi (P = 0.047) and primary melanoma (P = 0.001). Tip60 expression correlated with AJCC stages (I-II vs III-IV, P = 0.001) and tumor thickness (≤4.00 vs. &gt;4.00 mm, P = 0.037). Reduced Tip60 expression was associated with a poor five-year disease-specific survival in primary melanoma (P = 0.016) and metastatic melanoma patients (P = 0.027). Furthermore, Cox regression analyses indicated that Tip60 expression was an independent prognostic marker for primary (P = 0.002) and metastatic melanomas (P = 0.035). In conclusion, reduced Tip60 expression is significantly associated with thick primary melanoma and metastatic melanoma, as well as poor patient prognosis, suggesting that Tip60 may serve as a potential biomarker for advanced melanoma and patient outcome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2103. doi:10.1158/1538-7445.AM2011-2103
Abstract 2109: Tumor progression locus 2 (Tpl2) knockout mice have a dysregulation in COX-2 signaling in two-stage skin carcinogenesis
Authors: DeCicco-Skinner Kathleen L. , Nolan Sabrina , Dempsey Taylor , Trovato Erika , Weist Jonathan 
Published: July 2012

Abstract
Skin cancer is the most common form of cancer in the United States, with an estimated two million cases diagnosed annually. Inflammation is believed to be a critical component in skin cancer progression, and therefore understanding genes controlling inflammation is beneficial. MAP3K8 (Tpl2) is a protein kinase in the MAP Kinase signal transduction cascade. Previous research using a two-stage skin carcinogenesis model has revealed that Tpl2 -/- mice have significantly higher tumor incidence and inflammation than wild-type (WT) controls. Mechanistically, dysregulation in NF-κB signaling is a major contributor to the high degree of inflammation and tumorigenesis found in the Tpl2 -/- mice. Knockout animals have heightened NF-κB reporter activity, increased NF-κB dependent edema, and increased NF-κB nuclear localization. This study investigates how cyclooxygenase-2 (COX-2), an NF-κB regulated gene known to contribute to skin carcinogenesis, and COX-2 downstream factors might play a role in inflammation-mediated skin carcinogenesis in Tpl2 -/- mice. Keratinocytes from newborn WT or Tpl2 -/- mice were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for varying times over 24 hours. Western analysis revealed significant differences in COX-2 and COX-2 dependent prostanoids and prostanoid receptors. Additionally, in vivo experiments confirmed that COX-2 and COX-2 downstream factors were elevated in TPA-treated Tpl2 -/- skin, as well as in papillomas and squamous cell carcinomas from Tpl2-/- mice. These experiments illustrate that COX-2 induction in the absence of Tpl2 may be responsible for the increased tumorigenesis found in Tpl2-/- mice.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2109. doi:10.1158/1538-7445.AM2011-2109
Abstract 211: TIS21/BTG2/PC3 triggers cancer cell death, instead of cellular senescence, by enhancing proapoptotic gene expression at the downstream of p53
Authors: Devanand Preethi , Choi Ok Ran , Park Tae Jun , Lim In Kyoung 
Published: July 2012

Abstract
It has been known that cytoplasmic p53 regulates cell cycle arrest, apoptosis, autophage, and metabolism of human and animal cells in a transactivation-dependent manner. Wild type p53 induces senescence of EJ human bladder cancer cells, which carries oncogenic H-ras and mutant p53. Tumor supporessor, TIS21/BTG2/PC3, is one of the target genes regulated by wild type p53. Employing adenoviral vectors carrying p53(Ad-p53) and TIS21(Ad-TIS21) genes, we investigated effect of TIS21 on cancer cell senescence induced by p53 supplementation; Infection of EJ cells with p53 rapidly induced senescence phenotypes, such as cellular enlargement, inhibition of its growth, expressions of SA-[[Unsupported Character – Symbol Font ]]-galactosidase and SA-pErk1/2, and generation of reactive oxygen species, in addition to down-regulation of PARP and pRb expressions. A mechanism of the senescence was likely to be upregulations of H-ras and paxillin expressions by p53, evidenced by employing si-p53 RNA construct. On the contrary, the combined effect of p53 plus TIS21 significantly induced apoptosis of EJ cells rather than senescence, when evaluated by Annexin V expression, Calcein-AM and EhtD-1 double staining, increased expressions of proapoptotic genes and caspase 3 activity, whereas TIS21 alone failed to induce any changes, as compared with those of the control. p53 plus TIS21 significantly increased Bax and Apaf-1 expressions, whereas paxillin expression was clearly reduced as compared with those of p53 alone. When its mechanism was investigated, acetylation of p53 on K120 and K373 residues were found to be increased in addition to the significant translocation of p53 after coexpression of TIS21. We strongly suggest here that TIS21 is an endogenous cell death promoting gene at the downstream of p53 even in the expressions of oncogenic H-Ras and mutant p53.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 211. doi:10.1158/1538-7445.AM2011-211