bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 187: Clinically relevant efficacious doses of resveratrol induce changes in the AMPK/mTOR pathway, accompanied with senescence in preclinical models of colorectal cancer .
Authors: Kholghi Abeer O. 
Published: August 2014

Abstract
Resveratrol, a polyphenol present in red wine and peanuts exerts an array of beneficial effects, including anticancer activity and calorie restriction (CR) mimicry. Recent work from our laboratory has shown that low doses of resveratrol, comparable to amounts contained in a glass of red wine significantly reduced adenoma development in ApcMin mice when given with a high fat diet (Scott et al, unpublished). The protective effect was more pronounced than that caused by higher amounts, equivalent to doses used in clinical trials. The CR activity of resveratrol is mediated via the energy regulator AMP-activated kinase (AMPK). This study aims to investigate whether AMPK signalling contributes to the chemopreventive effect of resveratrol.
Intestinal mucosa from female ApcMin mice maintained on a high fat diet containing resveratrol (0.00007 or 0.014% in their diet) for 10 weeks was analysed by Western blotting to assess AMPK signalling, and the induction of autophagy and senescence. For more detailed mechanistic interrogation APC10.1 cells originally derived from adenomas of ApcMin mice were incubated with resveratrol (0.001-10μM) for 6 days and protein expression examined.
The extent of AMPK activation in vivo correlated with the degree of adenoma inhibition; AMPK expression and phosphorylation was evident in mucosa of resveratrol treated mice, but not in control animals, with highest levels in those that ingested the low dose. This chronic resveratrol treatment was also associated with increased expression of p21, a biomarker of senescence, particularly at the low dose. In APC10.1 cells resveratrol caused significant increases in AMPK phosphorylation at 0.01, 0.1 and 1μM, but not at 10μM, consistent with a bell-shaped dose-response. Activity was accompanied by significantly reduced phosphorylation of the mammalian target of rapamycin (mTOR), which is regulated by AMPK signalling, plus its downstream targets p70S6K and 4E-BP1. Furthermore, these concentrations also increased autophagy and senescence, as measured by LC3-II and p21 expression, respectively, and greater numbers of senescence-associated β-galactosidase positive cells.
The results suggest that activation of AMPK signalling and the induction of senescence may contribute to the cancer chemopreventive effects of resveratrol at dietary relevant intakes.
Citation Format: Abeer O. Kholghi. Clinically relevant efficacious doses of resveratrol induce changes in the AMPK/mTOR pathway, accompanied with senescence in preclinical models of colorectal 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 187. doi:10.1158/1538-7445.AM2013-187
Abstract 1873: Effect of intermittent calorie restriction on cancer stem cells.
Authors: Luo Yi , Kitadai Yasuhiko , Chihara Yoshitomo , Fujiwara Rina , Fujimoto Kiyohide , Kuniyasu Hiroki 
Published: August 2014

Abstract
Effect of intermittent calorie restriction (ICR) on cancer is controversial. We then examined the effect of ICR and food contents on cancer using mouse model. CT26 mouse colon cancer cells were inoculated into the back of syngeneic BALB/c mouse. A 24 hours-fasting was performed once a week for 4 weeks. A control diet and a high calorie diet were used for feeding. The body weight at week 4 of mice was not different among control diet (Group C), control diet+ICR (Group CI) and high fat diet+ICR (Group FI). The tumor weight, nodal metastasis and CD133-positive cancer stem cells (CSC) in the tumor were more pronounced in Group CI and FI than those in Group C and F. Blood CD133 mRNA levels after fasting breakage were increased in Group CI and FI. We have reported the prometastatic effect of trans fatty acids in colorectal cancer. Here effect of oral intake of trans fatty acids on tumor stem cells with ICR was examined using the same model. Mice fed with 10% elaidic acid diet with ICR- (Group E) or ICR+ (Group EI) were compared with Group C and CI. The tumor weight and tumor MIB1 index was Group EI, Group E, Group CI and Group C in high order. In Group EI, nucleostemin (NS)-positive tumor cells were transiently increased on the next day of ICR. During 12 ICR cycle, NS-positive CSCs were gradually increased in Group EI. These findings suggest that ICR might enhance cancer stem cell-activating factors.
Citation Format: Yi Luo, Yasuhiko Kitadai, Yoshitomo Chihara, Rina Fujiwara, Kiyohide Fujimoto, Hiroki Kuniyasu. Effect of intermittent calorie restriction on cancer stem cells. [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 1873. doi:10.1158/1538-7445.AM2013-1873
Abstract 1879: Myc induces lipogenesis and suppresses fatty acid oxidation in human P493-6 B-lymphoma cells.
Authors: Gouw Arvin Matthew , Mancuso Anthony , Hsieh Annie Lee , Altman Brian , Wolfgang Michael , Van Dang Chi 
Published: August 2014

Abstract
Myc has been known to control cell growth and proliferation through regulating thousands of genes, of which a substantial amount are involved in metabolism. We have previously shown that Myc increases ribosomal biogenesis, nucleotide metabolism, mitochondrial biogenesis, glycolysis and glutaminolysis in cancer cells. However, Myc's role in fatty acid metabolism is not well-documented, notwithstanding the expectation that Myc induction of cell growth must be accompanied by membrane biogenesis. Other studies have shown that fatty acids can be utilized as energy fuel by cancer cells or as building blocks for proliferation. The P493 human B cell line contains a tetracycline (Tet)-repressible human MYC transgene, permitting robust control of cell growth and proliferation through MYC. Having previously documented that Myc stimulates glucose and glutamine metabolism, we sought to determine whether Myc affects P493 use of fatty acids for oxidation and fatty acid synthesis. We found that resting P493 cells, in which ectopic MYC was off, can use labeled palmitate for respiration, while Myc activated P493 cells demonstrated an inability to oxidize palmitate. We also observe through microarray analysis and RT-PCR that Myc increases the levels of mRNAs for lipogenesis genes. Chromatin immunoprecipitation (ChIP) with an anti-Myc antibody documents that Myc binds to the promoters of lipogenesis genes. Moreover, immunoblot analyses with antibodies available for selected enzymes also indicate that Myc increases the protein levels of ACACA and FASN. Uniformly labeled 13C-glucose and 13C,15N-glutamine were found to be incorporated into lipids when Myc was induced in P493 cells. Cerulenin, an inhibitor of FASN, dramatically inhibits Myc-induced P493 cell proliferation. Similarly, TOFA-inhibition of ACACA suppresses P493 cell proliferation as well. Our data suggest that in P493 Burkitt lymphoma model cells, Myc inhibits fatty acid oxidation and upregulates fatty acid synthesis through transcription of target genes.
Citation Format: Arvin Matthew Gouw, Anthony Mancuso, Annie Lee Hsieh, Brian Altman, Michael Wolfgang, Chi Van Dang. Myc induces lipogenesis and suppresses fatty acid oxidation in human P493-6 B-lymphoma cells. [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 1879. doi:10.1158/1538-7445.AM2013-1879
Abstract 188: 4-methylumbelliferone: Dietary supplement turned chemo-preventive and anti-metastatic agent for prostate cancer.
Authors: Yates Travis , Lopez Luis , Hupe Marie , Ortiz Nicolas , Lokeshwar Vinata B. 
Published: August 2014

Abstract
INTRODUCTION: Hyaluronic acid (HA), a glycosaminoglycan, is associated with prostate cancer (PCa) progression and metastasis. 4-methylumbelliferone (4-MU) is a HA-synthesis inhibitor and we have shown antitumor and anti-invasive effects of 4-MU on PCa cells in vitro and in xenografts. In this study we evaluated the efficacy of 4-MU to prevent PCa growth and metastasis in the TRAMP model. We also evaluated the effects of 4-MU on epithelial-mesenchymal transition (EMT).
METHODS: TRAMP mice (n = 8-11/group) were treated with vehicle or 4-MU (450 mg/kg) by starting stage-specific treatment at 8 (PIN stage), 12 (adenocarcinoma) and 22 (invasive carcinoma) wks of age. At 28 wks, 50% of animals in 4-MU treated groups were sacrificed and the other 50% were left untreated up to 52 wks. At necropsy prostate (P) and seminal vesicles (SV) were weighed, tissues were analyzed by histology, immunohistochemistry and quantitative PCR for EMT markers and serum chemistry was evaluated. PC3-ML cells treated with 4-MU were analyzed for EMT markers.
RESULTS: At 28 wks, 100% of vehicle treated mice developed prostate tumors, but tumor growth and progression was inhibited in all 4-MU treated groups; P+SV weight (g): vehicle: 3.2±2.9; 8 wk: 0.43±0.14; 12 wk: 0.35±0.04; 22 wk: 1.0±0.35 g. The P+SV weight in TRAMP mice at 22 wks of age was 0.9±0.04, showing that late stage administration of 4-MU halted further tumor progression. Animals in 8 and 12 wk groups remained tumor free until 52 wk and 44 wk respectively. While 55% of vehicle treated animals developed metastasis, none of the treated groups had metastasis. No serum/organ toxicity or weight loss was observed in the treatment groups. HA, HA receptors (CD44, RHAMM) and EMT markers (β-catenin, Zeb2) were downregulated (&gt;2-fold), but E-cadherin was upregulated (4-fold) in the treatment groups. 4-MU treatment (0-60 μg/ml) similarly modulated the expression of EMT markers and HA receptors in PC3-ML cells.
CONCLUSION: 4-MU is a promising non-toxic, oral chemopreventive agent, which inhibits PCa growth and metastasis by plausibly abrogating HA-signaling and reversing EMT.
Support: R01 CA 123063-04 (VBL); R01 CA 72821-11 (VBL)
Citation Format: Travis Yates, Luis Lopez, Marie Hupe, Nicolas Ortiz, Vinata B. Lokeshwar. 4-methylumbelliferone: Dietary supplement turned chemo-preventive and anti-metastatic agent for prostate 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 188. doi:10.1158/1538-7445.AM2013-188
Abstract 1888: Metabolomic analysis provides insights into uncoupling-induced cancer resistance in the K5-UCP3 mouse model.
Authors: Solmonson Ashley , Keaton Mignon , Nowinski Sara M. , Morin-Kensicki Elizabeth , Mills Edward M. 
Published: August 2014

Abstract
Metabolic reprogramming is a hallmark of tumorigenesis and malignancy across a variety of cancer types. Reduced oxidative phosphorylation and increased ATP synthesis by glycolytic upregulation is thought to provide both the energy and metabolic precursors necessary to meet the increased biosynthetic and energetic demands associated with malignancy. We hypothesized that since uncoupling protein 3 (UCP3) dissipates the mitochondrial electrochemical proton gradient, it may lead to the consumption or depletion of biosynthetic substrates necessary for carcinogenesis. In support, previous studies have shown that mice expressing a keratin 5-UCP3 transgene are completely resistant to chemically- and Ras-induced skin carcinogenesis, however the metabolic consequences of UCP3 overexpression in relation to cancer resistance are unclear. To examine the metabolic changes associated with UCP3 expression and this profound skin cancer resistance, we performed metabolomic analysis of more than 350 metabolites in epidermis from K5-UCP3 and wild type FVB/N littermate mice. Results of this analysis show significant UCP3-dependent changes in metabolites indicative of increased energy harvesting via glycolysis, beta-oxidation and branched chain amino acid metabolism. Consistent with decreased energy reserve, K5-UCP3 epidermis exhibits increased uncoupled respiration, decreased ATP and increased AMP levels, which correspond to increased AMP Kinase (AMPK) activation (Thr172 phosphorylation). Taken together, these data suggest that uncoupling proteins might function to oppose the metabolic demands of tumorigenesis and suggest that targeting mitochondrial uncoupling may be a novel and effective strategy in cancer prevention and treatment.
Citation Format: Ashley Solmonson, Mignon Keaton, Sara M. Nowinski, Elizabeth Morin-Kensicki, Edward M. Mills. Metabolomic analysis provides insights into uncoupling-induced cancer resistance in the K5-UCP3 mouse model. [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 1888. doi:10.1158/1538-7445.AM2013-1888
Abstract 1903: Up-regulation of vitamin B1 homeostasis genes in breast cancer.
Authors: Zastre Jason , Hanberry Brad , Sweet Rebecca , McGinnis Cary , Venuti Kristen , Bartlett Michael , Govindarajan Raj 
Published: August 2014

Abstract
Malignant cells exhibit alterations in metabolic enzymes requiring an adequate supply of cofactors to support enzymatic activity. In particular, Vitamin B1 (thiamine) is an important component of cellular growth and metabolism within all cells, functioning as an essential enzyme cofactor in key metabolic pathways within in the glycolytic network. Intracellular availability of thiamine is facilitated by the activity of thiamine transporters and the conversion of thiamine to the active coenzyme, thiamine pyrophosphate (TPP) by thiamine pyrophosphokinase (TPK1). Therefore, the objective was to establish if the cellular determinants regulating thiamine homeostasis differ between breast cancer and normal breast epithelia. This work will aid in linking the metabolic phenotype of cancer cells with the adaptive regulation of thiamine homeostasis. This may provide a molecular basis for dietary interventions and new therapeutic targets directed towards cancer cell metabolism.
Methods: cDNA arrays of breast cancer and normal breast tissues were employed to determine expression of SLC19A2, SLC19A3, SLC25A19 and TPK-1. Western blotting was used to determine whole cell protein expression. To test the extent of cell surface localization of the transporters, cell surface proteins were biotinylated and run on Western Blot. Transport assays were used to quantify thiamine transport and free thiamine levels in breast cancer cell lines compared to human mammary epithelial cells (HMEC).
Results: SLC19A2, SLC25A19 and TPK-1were found to be significantly up-regulated in clinical tissues and breast cancer cell lines 6.48 (P=0.0013), 5.97 (P=0.0003), and 2.33 (P=0.0063) folds, respectively. Additionally, thiamine transporters THTR1 and THTR2 exhibited different cellular localization and expression depending on the ER status of the cancer cell. The increase in thiamine homeostasis genes correlated with an increase in intracellular free thiamine levels but not with the coenzyme TPP.
Conclusions: Overall, these findings demonstrate an adaptive response by breast cancer cells to bolster an increase in the cellular availability of thiamine.
Citation Format: Jason Zastre, Brad Hanberry, Rebecca Sweet, Cary McGinnis, Kristen Venuti, Michael Bartlett, Raj Govindarajan. Up-regulation of vitamin B1 homeostasis genes 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 1903. doi:10.1158/1538-7445.AM2013-1903
Abstract 1908: 19q13.2 amplification occurs in a subset of SMAD4-deficient pancreatic cancers.
Authors: Min Bosun , Lai Albert , Bardeesy Nabeel , Deshpande Vikram 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. The PDAC genomes show evidence of high genomic instability leading to complex genomic rearrangements and copy number alterations. Major genetic events involved in PDAC progression have been characterized, but the subsequent alterations that contribute to different tumor behavior or patient outcomes are not well understood. Smad4 tumor suppressor gene mutation or deletion in pancreatic cancer correlates with metastatic disease and poorer patient outcome. We found that in a subset of PDACs with Smad4 expression loss, the chromosomal region 19q13.2 is focally amplified. Genomic amplifications found in cancers have been shown to contain driver genes that contribute to tumorigenesis. We are currently investigating the contribution of 19q13.2 amplicon resident genes in pancreatic cancer cell growth. Our characterization of a cancer amplicon in relation to known major genetic events in pancreatic cancer revealed that the 19q13.2 amplicon is closely associated with a subset of SMAD4-deficient tumors. Through additional in-depth tumor analyses we may better understand the heterogeneity and complexity of PDAC biology.
Citation Format: Bosun Min, Albert Lai, Nabeel Bardeesy, Vikram Deshpande. 19q13.2 amplification occurs in a subset of SMAD4-deficient pancreatic cancers. [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 1908. doi:10.1158/1538-7445.AM2013-1908
Abstract 1922: Plasminogen activator inhibitor type-1 (PAI-1) enhances bladder cancer tumor progression.
Authors: Gomes Evan , Goodison Steven , Miyake Makito , Ross Shanti , Zhang Ge , Rosser Charles 
Published: August 2014

Abstract
Introduction: Bladder cancer (BCa) is among the five most common malignancies worldwide and has the highest recurrence rate of any tumor type. BCa biology is poorly understood and early detection remains one of the most urgent issues in BCa research. Previously we have identified a preliminary molecular signature of BCa in voided urine samples from BCa patients. Our results revealed aberrant overexpression of the serine protease inhibitor (serpin) plasminogen activator inhibitor type-1 (PAI-1), both at the genomic and protein level. Increasing evidence indicate that elevated levels of PAI-1 correlates to a poor prognosis in many tumor types including breast, colorectal, gastric, ovarian, and more recently bladder cancer. PAI-1 has emerged as a potential target for BCa treatment and the aim of this study is to provide a greater understanding of its role in bladder cancer progression.
Methods: PAI-1 expression levels in UROtsa (benign urothelial cell), KU7 (low-grade papillary urothelial cancer cell), and UMUC14 and T24 (high-grade invasive urothelial cancer cell lines) was tested by real-time PCR (RTPCR) and Western blot analysis. Secreted PAI-1 levels were measured by ELISA. KU7 stable clones overexpressing PAI-1 was established by transfection of plasmid DNA encoding human PAI-1. T24 and UMUC14 stable clones with shRNA knockdown of PAI-1 were established by infection with retroviral particles. Cell proliferation, migration, invasion, and apoptosis assays were performed in stable clones.
Results: RTPCR analysis revealed an increase of PAI-1 in T24 and UMUC14 cells (27.9 and 5.2 times, respectively) while KU7 cells exhibited significantly reduced levels as compared to the UROtsa control. Similar results were observed for PAI-1 protein concentrations in cell culture supernatants and western blot analysis. While overexpression of PAI-1 in KU7 cells promoted an increase in proliferation, migration and invasion, these were significantly reduced upon inactivation of PAI-1 in T24 and UMUC14 cells stably expressing shRNA PAI-1. Loss of PAI-1 function also led to a substantial increase in apoptotic cell death.
Conclusions: These results suggest that PAI-1 overexpression in BCa promotes tumor progression and therapeutic strategies targeting PAI-1 may serve clinically beneficial outcomes.
Funding provided by research grants from Florida Department of Health James and Esther King Team Science Award 10KT-01 (CJR) and National Cancer Institute RO1 CA116161 (SG).
Citation Format: Evan Gomes, Steven Goodison, Makito Miyake, Shanti Ross, Ge Zhang, Charles Rosser. Plasminogen activator inhibitor type-1 (PAI-1) enhances bladder cancer tumor progression. [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 1922. doi:10.1158/1538-7445.AM2013-1922
Abstract 1923: Constitutional mismatch repair-deficiency syndrome is a rare cause of cancer even in a highly consanguineous population.
Authors: Bu Rong , Siraj Abdul K. , Bavi Prashant , Belgaumi Asim , Al-Haqawi Wael , Al-Dayel Fouad , Uddin Shahab , Alkuraya Fowzan S. , Al-Kuraya Khawla S. 
Published: August 2014

Abstract
Background:
Biallelic germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 cause a recessive childhood cancer syndrome characterized by early onset malignancies and signs reminiscent of neurofibromatosis type 1 (NF1). This syndrome is known as constitutional mismatch repair-deficiency (CMMR-D) syndrome. Because consanguinity unmasks autosomal recessive disorders, we hypothesized that the frequency of CMMR-D is inflated in the highly consanguineous population of Saudi Arabia.
Methods:
372 patient samples from Saudi Arabia that cover the tumor spectrum of CMMR-D syndrome were analyzed for biallelic germline mutations in the MLH1, MSH2, MSH6 and PMS2 with the use of direct genomic sequencing.
Results:
None of the 372 patients involved in the study was found to have biallelic pathological mutations of MLH1, MSH2, MSH6 or PMS2.
Conclusion:
CMMR-D is exceptionally rare among pediatric cancer patients and adult early onset cancer patients, even in the highly consanguineous Saudi population. Our findings suggest that larger cohorts will be needed, particularly in outbred populations, to determine the frequency of CMMR-D and that routine screening for this syndrome among cancer patients is not warranted.
Citation Format: Rong Bu, Abdul K. Siraj, Prashant Bavi, Asim Belgaumi, Wael Al-Haqawi, Fouad Al-Dayel, Shahab Uddin, Fowzan S. Alkuraya, Khawla S. Al-Kuraya. Constitutional mismatch repair-deficiency syndrome is a rare cause of cancer even in a highly consanguineous population. [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 1923. doi:10.1158/1538-7445.AM2013-1923