bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5419: Thiamine deficiency induces HIF-1 α stabilization and target gene expression.
Authors: Sweet Rebecca , Lim Lauren , Zastre Jason 
Published: August 2014

Abstract
Introduction: Thiamine deficiencies have been reported in a number of common pathologies including diabetes, neurodegenerative disorders and in particular, cancer. Deficiencies can arise due to drug mediated reductions in cellular availability of thiamine or due to limited diffusion into solid tumors. Biochemically, a metabolic consequence of thiamine deficiency is a reduction in enzyme activity and expression of pyruvate dehydrogenase complex (PDH), which converts pyruvate to acetyl-CoA. Evidence suggests that trans-activation of hypoxia inducible factor 1-alpha (HIF-1α) regulated genes is mediated through stoichiometric changes in the metabolic intermediate pyruvate, independent of low oxygen termed pseudo-hypoxia. The resulting dysfunction of PDH and accumulation of pyruvate during TD may facilitate a pseudo-hypoxic state and mediate trans-activation of HIF-1α regulated genes. Therefore, we hypothesize that thiamine deficiency induces a pseudo-hypoxic state resulting in a stabilization of HIF-1α.
Methods: The impact of TD treatments on cellular pyruvate levels was determined after 48h of TD treatment using a pyruvate assay. Protein expression of HIF-1α was assessed in nuclear lysates of SK-N-BE cells treated with 1% O2 and TD for 12, 24, and 48h by Western blot. Expression of the known HIF-1α regulated gene, GLUT1 was measured by qRTPCR after 12, 24 and 48h hypoxia (1% O2) and thiamine depletion.
Results: An approximately 2 fold increase in cellular pyruvate was observed after 48h of TD exposure. A corresponding increase in HIF-1α protein expression in both 1% O2 and TD was found after 48h exposure. SK-N-BE cells demonstrated a 6 and 10 fold increase in expression of GLUT1 and SLC19A3, respectively after 48h of 1% O2 exposure. TD treatment exhibited an approximately 2 fold increase in expression of both GLUT1 and SLC19A3 after 48h treatments.
Conclusions: An increase in pyruvate production and the induction of HIF-1α protein expression after TD treatment suggests the role of TD acting as a feed forward mechanism for HIF-1α stabilization and gene regulation. These results demonstrate nutritional regulation of the pro-oncogenic transcription factor, HIF-1α and an important connection of cellular thiamine to adaptive glycolytic metabolism.
Citation Format: Rebecca Sweet, Lauren Lim, Jason Zastre. Thiamine deficiency induces HIF-1 α stabilization and target gene expression. [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 5419. doi:10.1158/1538-7445.AM2013-5419
Abstract 5420: Normal mammary epithelial mitochondria introduced into human breast cancer cells results in inhibition of proliferation and increased drug sensitivity of the MCF-7 breast cancer cell line.
Authors: Elliott Robert L. , Jian Xian P. , Head Jonathan F. 
Published: August 2014

Abstract
Warburg in the 1920s postulated that mitochondrial dysfunction alters metabolism in cancer. He observed in cancer cells aerobic glycolysis, which is the conversion of glucose to lactic acid in the presence of oxygen, the so called “Warburg effect” [1]. Mitochondrial dysfunction of cancer cells includes increased aerobic glycolysis, elevated levels of ROS, decreased apoptosis, and resistance to chemotherapeutic agents. We reported on the ultrastructural observations of mitochondria in human breast carcinoma cells [2]. There were three distinct groups: (1) mitochondria absent, (2) mitochondria present, (3) mitochondria present but sparse and abnormal. Tumors in the absent group were more anaplastic, aggressive, and resistant to treatment. We hypothesized that the introduction of normal mitochondria into cancer cells might restore mitochondrial function and inhibit cancer cell growth, and reverse chemoresistance. First we tested if mitochondria of normal mammary epithelial MCF-12A cells could enter into cultured human cancer cells. Then we determined if introducing normal mitochondria into cancer cells would inhibit proliferation. Finally we determined if addition of normal mitochondria increases the sensitivity of human breast cancer MCF-7 cells to chemotherapy. We found JC-1 stained mitochondria from normal mammary epithelial MCF-12A cells can enter into the cancer cell lines MCF-7, MDA-MB-231, and NCI/ADR-Res, but cannot enter normal MCF-12 A cells. The normal mitochondria from normal MCF-12 A cells suppressed the proliferation of MCF-7 and NCI/ADR-Res cells in a dose dependent pattern, but did not affect the proliferation of normal MCF-12A cells. The normal mitochondria from normal MCF-12A cells increased the sensitivity of human breast cancer MCF-7 cells to doxorubicin, Abraxane, and carboplatin. In conclusion the introduction of normal mammary mitochondria into human cancer cells inhibits cancer cell proliferation and increases the sensitivity of the MCF-7 human breast cancer cells to doxorubicin, Abraxane, and carboplatin. This phenomenon has never been reported, and the results support the role of mitochondrial dysfunction in cancer and suggest the possible use of targeted mitochondria as an adjunct to cancer therapeutics.
Citation Format: Robert L. Elliott, Xian P. Jian, Jonathan F. Head. Normal mammary epithelial mitochondria introduced into human breast cancer cells results in inhibition of proliferation and increased drug sensitivity of the MCF-7 breast cancer cell line. [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 5420. doi:10.1158/1538-7445.AM2013-5420
Abstract 5428: Rewiring of glucose metabolism in cancer.
Authors: Locasale Jason W. 
Published: August 2014

Abstract
This seminar topic focuses on the role glucose metabolism in cancer biology. A common theme within this biology is a rewiring of metabolism to support and drive these processes. I will discuss how changes in the metabolism of cancer cells alters the physic-chemical properties of the metabolic network. At the core of this effort lies the utilization of computational modeling and mass spectrometry. Using these tools, we have studied the effects of an alternative glycolytic pathway observed in proliferating cells that we recently identified. These efforts have enumerated several principles of glycolytic regulation in growing cells. We have also defined and characterized a metabolic pathway that is genetically selected for and drives the development of human cancer. This pathway involves the diversion of glycolytic flux into de novo serine metabolism through phosphoglycerate dehydrogenase (PHGDH). This direction has also led us to the study of how metabolism can regulate pluripotency and cell fate determination. Together, these findings define a systems biology approach through combining these mathematical tools with an integration of genetics, biochemistry, cell biology, and metabolomics.
Citation Format: Jason W. Locasale. Rewiring of glucose metabolism in cancer. [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 5428. doi:10.1158/1538-7445.AM2013-5428
Abstract 5430: Docosahexaenoic acid attenuates glycolytic metabolism and the Warburg phenotype by targeting hypoxia inducible factor 1 alpha in breast cancer.
Authors: Mouradian Michael , Kikawa Keith D. , Pardini Ronald S. 
Published: August 2014

Abstract
Dietary factors have been estimated to account for approximately 30-40 percent of cancer incidence and research has shown that high fat diets rich in n-3 polyunsaturated fatty acids (PUFAs) are associated with lower cancer occurrences, including breast cancer. The glycolytic switch, known as the Warburg Effect, is observed in many malignant models, which results in a unique metabolic shift in energy metabolism where tumor cells increase anaerobic glycolysis even in the presence of normal oxygen levels. In our laboratory, we have shown that the n-3 PUFA, docosahexaenoic acid (DHA; C22:6), significantly decreases total cellular ATP and the transcriptional activity and protein levels of hypoxia-inducible factor 1 alpha (HIF-1α), a major contributor to the Warburg phenotype. In this project, we set out to determine if DHA is responsible for attenuating the Warburg Effect through a HIF-1α-dependent mechanism. Alterations in glucose uptake and usage upon supplementation with DHA were examined in vitro in the breast cancer BT-474, MDA-MB-231, and non-transformed MCF-10A cell lines. Total glucose transporter 1 (GLUT 1) protein levels were determined in each cell line. No change was seen upon DHA supplementation in the MDA-MB-231 cell line, which may be due to overexpression of GLUT 1. However, GLUT 1 protein levels were significantly down in response to DHA treatment in the BT-474 cell line. We also observed significant decreases in glucose consumption through glycolysis and lactate production in the BT-474 and MDA-MB-231 cell lines upon DHA supplementation. However, no change was seen in the non-transformed cell line MCF-10A, suggesting that DHA is having anti-glucose-metabolism effects specifically on cancer cells, but not on non-transformed cells. Moreover, HIF-1α small interfering RNA (siRNA) experiments showed a similar trend in GLUT 1 expression and glycolytic capacity in the BT-474 and MDA-MB-231 cell lines, suggesting that DHA is exerting some of its anti-cancer effects through HIF-1α. Based on these findings, changes in glucose transporter expression and glucose usage likely contribute to the impaired growth and survival of malignant cell lines supplemented with DHA. Currently, therapies are being developed to target the Warburg Effect in the treatment of cancer and DHA could likely enhance such therapies.
Citation Format: Michael Mouradian, Keith D. Kikawa, Ronald S. Pardini. Docosahexaenoic acid attenuates glycolytic metabolism and the Warburg phenotype by targeting hypoxia inducible factor 1 alpha in breast cancer. [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 5430. doi:10.1158/1538-7445.AM2013-5430
Abstract 5440: Analyzing in vivo conformational changes of a transcription factor, c-Myb, using fluorescence resonance energy transfer (FRET) technology.
Authors: George Olivia L. , Ness Scott A. 
Published: August 2014

Abstract
The c-myb proto-oncogene was first identified as the normal cellular counterpart to the v-myb oncogene identified in Avian Myeloblastosis virus (AMV), a retrovirus that transforms immature hematopoietic cells in tissue culture and induces leukemias in animals. However, the normal c-Myb protein is not oncogenic, in part because of conformational and auto-inhibitory interactions that keep its transforming activity in check. The c-Myb protein functions as both an activator and repressor of transcription and its regulation involves sequences found in the negative regulatory domain. We hypothesize that c-Myb protein undergoes conformational changes due to post-translational modifications and protein interactions that may help direct it to different sets of target gene promoters. In addition, there could also be upstream signaling pathways, for example the signals that direct cells either to proliferate or to undergo differentiation, that could contribute to its transforming potential. To address this, we are utilizing FRET technology to elucidate whether the intramolecular interactions of c-Myb or its interactions with various co-factors and co-activators change in vivo in response to extracellular signals that trigger a switch from proliferation to differentiation. The goal is to determine how the conformations and protein-protein interactions of c-Myb change in cells in response to signals that control cell fate.
Citation Format: Olivia L. George, Scott A. Ness. Analyzing in vivo conformational changes of a transcription factor, c-Myb, using fluorescence resonance energy transfer (FRET) technology. [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 5440. doi:10.1158/1538-7445.AM2013-5440
Abstract 5441: The involvement of MSK1 in non-canonical activation of NF-KB in the late phase of UVB irradiation.
Authors: Carpenter Oliver L. 
Published: August 2014

Abstract
Nuclear Factor Kappa-B (NF-KB) is a transcription factor that plays a crucial role in controlling expression of genes involved in the immune and inflammatory responses as well a being a key component in the onset of a larger number of cancers. One activator of NF-KB that has been studied, but still remains controversial, is that of ultraviolet B light (UVB). In this study we demonstrate that mitogen- and-stress activated protein kinase (MSK1) is responsible for a non-canonical late-phase activation of NF-KB. Following UVB irradiation (50 mJ/cm2) MSK1 is activated via phosphorylation at both 6 and 24 h time points. Investigations into the signaling pathways upstream of MSK1 through the use of specific inhibitors for mitogen-activated protein kinase kinase (MEK)(PD 98059) and p38 (SB 203580) revealed that both kinases are required for full phosphorylation during the late-phase (24 h) while p38 is predominately responsible for phosphorylation during the early-phase (6 h). Electromobilty shift assays (EMSA) for NF-KB binding affinity showed that inhibition of MSK1 via inhibitor H89 resulted in a marked reduction in binding affinity. Inhibition of p38 also coincided with a reduction in NF-KB binding affinity. Interestingly, supershift assays implicate that the p65 isoform of NF-KB is predominantly involved in late-phase activation in response to UVB irradiation. Analysis of cell viability showed that decreased viability was correlated with MSK1 inhibition and decreased NF-KB binding affinity. Together, the results of these studies shed light onto a novel pathway of MSK1 mediated late-phase activation of NF-KB in response to UVB irradiation.
Citation Format: Oliver L. Carpenter. The involvement of MSK1 in non-canonical activation of NF-KB in the late phase of UVB irradiation. [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 5441. doi:10.1158/1538-7445.AM2013-5441
Abstract 5442: The role of ATF3 in arsenic-induced GADD45 expression.
Authors: Shi Qiwen , Bhatia Deepak , Sutariya Vijaykumar B. 
Published: August 2014

Abstract
GADD45 (growth arrest and DNA damage inducible gene 45), an effector of G2/M checkpoint, is induced by trivalent arsenic (As3+) in human bronchial epithelial cell line, BEAS-2B. In the present study, we investigated the regulation of ATF3 (activating transcription factor 3) on GADD45 with As 3+ treatment. We demonstrated that As3+ induced ATF3 expression, at both mRNA and protein level, and the induction was reduced by p38 and JNK inhibition, but not affected by PI3K and ERK inhibition. Luciferase assay also confirmed As3+ involvement in ATF3 transcriptional regulation. Moreover, silencing of ATF3 downregulated As3+-induced expression of GADD45 and chromatin immunoprecipitation suggested that ATF3 acted as an activator of GADD45 transcription in the presence of As3+. Taken together, our data indicated that the increase of GADD45 in response to As3+ was mediated by ATF3.
Citation Format: Qiwen Shi, Deepak Bhatia, Vijaykumar B. Sutariya. The role of ATF3 in arsenic-induced GADD45 expression. [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 5442. doi:10.1158/1538-7445.AM2013-5442
Abstract 5447: Phosphorylation status of Ascl1 regulates neuroblastoma self-renewal and differentiation.
Authors: Wylie Luke A. , Thiele Carol J. , Philpott Anna 
Published: August 2014

Abstract
Neuroblastoma (NB) is a tumor of infancy that accounts for 15% of all pediatric cancer mortality. NB bares striking similarity to undifferentiated neuroblasts of the sympathetic nervous system in gene expression profiles and histological appearance. In most neuroblastoma tumors, the cell cycle is hyperactive due to overexpression of cyclin D1 and amplification of MYCN. However, retinoic acid (RA) induces differentiation and cell cycle exit of some NB cell lines in vitro and provides significant benefit to patients in the clinic. As neuroblastoma appears to result from sustained proliferation and inhibition of differentiation, we sought to understand how cell cycle and differentiation are linked within NB. We focused our efforts on Ascl1, a proneural transcription factor that is both necessary and sufficient for neural differentiation of noradrenergic neurons and has been shown to be regulated by the cell cycle. Paradoxically, Ascl1 is both highly expressed and associated with poor prognosis in NB. However, we hypothesized that Ascl1 phosphostatus critically regulates its ability to induce differentiation.
We show that Ascl1 is highly expressed and phosphorylated across multiple NB cell lines and is largely phosphorylated by CDKs. Phosphorylated Ascl1 actively promotes the G1-S transition by upregulating E2f, Skp2, and Cdk2. These targets all promote CDK activity, further maintaining Ascl1 phosphorylation. However, a phosphomutant form of Ascl1, where putative CDK sites are mutated, arrests cells in the G1 phase by preferentially upregulating Ebf3 and p27. These targets inhibit CDK activity promoting Ascl1 dephosphorylation and further upregulation of Ebf3 and p27. We propose a model whereby Ascl1 sits between two positive feedback loops, both forming a critical link between cell cycle and differentiation, but also as an agent to commit cells to either a self-renewing undifferentiated state or a postmitotic differentiated state.
Given this model, we hypothesized that pharmacologic inhibition of CDK activity when combined with a pro-differentiation agent such as RA would synergistically cause differentiation in neuroblastoma. Indeed, CDK inhibitor and RA combination treatment causes increased differentiation in RA-susceptible cell lines and induces differentiation in RA-resistant cell lines. Given that most neuroblastoma tumors have an overactive cell cycle and also highly express Ascl1, combination therapy of CDK inhibitor and RA may provide generalized benefit to NB patients.
Citation Format: Luke A. Wylie, Carol J. Thiele, Anna Philpott. Phosphorylation status of Ascl1 regulates neuroblastoma self-renewal 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 5447. doi:10.1158/1538-7445.AM2013-5447
Abstract 5458: Individual and combined activities of STAT1 and STAT3 have prognostic relevance for the progression of colorectal carcinoma.
Authors: Gordziel Claire , Nivarthi Harini , Knösel Thomas , Dolznig Helmut , Moriggl Richard , Friedrich Karlheinz 
Published: August 2014

Abstract
Aberrant activities of JAK/STAT signalling pathways have been implicated in the development and spread of various cancer entities, among them colorectal carcinoma (CRC). By immunohistochemical analysis of a tissue microarray covering more than 400 CRC biopsies from patients with full clinical documentation, the expression and activity status of STAT1 and STAT3 was determined. Results were correlated with clinical information. A significant association of high STAT1 activity (as indicated by nuclear location) with longer patient overall survival was observed. Unexpectedly, strong STAT3 expression in surgical specimens could be clearly correlated with an increase in median overall survival by about 30 months.
Interestingly, combined consideration of STAT1/3 expression and activity levels in CRC specimens revealed patterns that match the clinical outcome with statistical significance. For instance, tumors with concomitant absence of STAT1 and STAT3 have a worse prognosis, while high STAT1 activity along with low STAT3 activity proved associated with longer patient survival.
To address the signal transduction background of these findings, STAT1/3 expression was experimentally modified in
CRC cell lines and effects on the growth of xenograft tumors were studied. Mimicking
STAT1/3 patterns from patient biopsies in xenografts resulted in alterations in tumor growth well corresponding to clinical data. From these experiments we draw the conclusions that the ratio of nuclear STAT1/STAT3 is a determinant of colon carcinoma progression.
Supported by: Deutsche Krebshilfe, IZKF Jena, European Regional Development Fund ERDF
Citation Format: Claire Gordziel, Harini Nivarthi, Thomas Knösel, Helmut Dolznig, Richard Moriggl, Karlheinz Friedrich. Individual and combined activities of STAT1 and STAT3 have prognostic relevance for the progression of colorectal carcinoma. [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 5458. doi:10.1158/1538-7445.AM2013-5458
Abstract 547: Inhibition of PI 3-K isoforms lead to reactivation of Akt signaling in a subset of breast cancer cell lines.
Authors: Collmann Emilie , Toker Alex 
Published: August 2014

Abstract
The aggressive behavior of malignant breast cancer cells is determined by a complex array of signaling pathways that regulate functions such as growth, survival, and migration. Production of phosphatidylinositol-3,4,5-P3 (PIP3) by phosphoinositide 3-kinase (PI 3-K) results in activation of downstream targets including the protein kinase Akt that plays critical roles in cell survival and growth. Recent studies have highlighted alternate, PI 3-K independent pathways often associated with malignancy that lead to Akt reactivation. The goal of our studies is to investigate the role of PI 3-K catalytic subunits in Akt reactivation in breast cancer.
Surprisingly, knock-down of the catalytic subunit of class I PI 3-K PIK3CA actually enhances phosphorylation of Akt, as well as the downstream targets S6K1 and GSK3β in a subset of triple negative breast cancer (TNBC) cell lines. The resulting increase in Akt phosphorylation is mTORC2-dependent and is insensitive to the class I PI 3-K inhibitors. Rescue experiments with wild type PIK3CA alleles reveal a further enhancement of Akt phosphorylation, when compared to PIK3CA knock-down alone. Moreover, silencing of distinct class I subunits PIK3CB and PIK3CD also enhanced Akt phosphorylation in TNBC. However, this effect is not universal and is not observed in numerous other breast cancer cell lines, or using specific PIK3CA inhibitors. This reactivation of Akt signaling suggests the interruption of a feedback loop similar to the mTOR-S6K-IRS1 negative feedback loop. It also indicates specific roles for individual PI 3-K isoforms in breast cancer and dependent on the mutational status of PTEN and PIK3CA.
This research is supported by Susan G. Komen for the Cure postdoctoral fellowship KG111139 to EC and AT.
Citation Format: Emilie Collmann, Alex Toker. Inhibition of PI 3-K isoforms lead to reactivation of Akt signaling in a subset of breast cancer cell lines. [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 547. doi:10.1158/1538-7445.AM2013-547