Publications by authors named "Lauren M Malone"

3 Publications

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Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer.

Cancer Prev Res (Phila) 2011 Jul 18;4(7):1041-51. Epub 2011 May 18.

Department of Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas, USA.

Etiologic factors for pancreatic cancer, the 4th deadliest malignant neoplasm in the United States, include obesity and abnormal glucose metabolism. Calorie restriction (CR) and rapamycin each affect energy metabolism and cell survival pathways via inhibition of mammalian target of rapamycin (mTOR) signaling. By using a Panc02 murine pancreatic cancer cell transplant model in 45 male C57BL/6 mice, we tested the hypothesis that rapamycin mimics the effects of CR on pancreatic tumor growth. A chronic regimen of CR, relative to an ad libitum-fed control diet, produced global metabolic effects such as reduced body weight (20.6 ± 1.6 g vs. 29.3 ± 2.3 g; P < 0.0001), improved glucose responsiveness, and decreased circulating levels of insulin-like growth factor (IGF)-1 (126 ± 8 ng/mL vs. 199 ± 11 ng/mL; P = 0.0006) and leptin (1.14 ± 0.2 ng/mL vs. 5.05 ± 1.2 ng/mL; P = 0.01). In contrast, rapamycin treatment (2.5 mg/kg intraperitoneal every other day, initiated in mice following 20 weeks of ad libitum control diet consumption), relative to control diet, produced no significant change in body weight, IGF-1 or leptin levels, but decreased glucose responsiveness. Pancreatic tumor volume was significantly reduced in the CR group (221 ± 107 mm(3); P < 0.001) and, to a lesser extent, the rapamycin group (374 ± 206 mm(3); P = 0.04) relative to controls (550 ± 147 mm(3)), and this differential inhibition correlated with expression of the proliferation marker Ki-67. Both CR and rapamycin decreased phosphorylation of mTOR, p70/S6K, and S6 ribosomal protein, but only CR decreased phosphorylation of Akt, GSK-3β, extracellular signal regulated kinase/mitogen-activated protein kinase, and STAT3(TYR705). These findings suggest that rapamycin partially mimics the anticancer effects of CR on tumor growth in a murine model of pancreatic cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-11-0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131470PMC
July 2011

Genetic reduction of insulin-like growth factor-1 mimics the anticancer effects of calorie restriction on cyclooxygenase-2-driven pancreatic neoplasia.

Cancer Prev Res (Phila) 2011 Jul 18;4(7):1030-40. Epub 2011 May 18.

Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.

Risk of pancreatic cancer, the fourth deadliest cancer in the United States, is increased by obesity. Calorie restriction (CR) prevents obesity, suppresses carcinogenesis in many models, and reduces serum levels of IGF-1. In the present study, we examined the impact of CR on a model of inflammation-associated pancreatitis and pancreatic dysplasia, with a focus on the mechanistic contribution of systemic IGF-1. Administration of a 30% CR diet for 14 weeks decreased serum IGF-1 levels and hindered pancreatic ductal lesion formation and dysplastic severity, relative to a higher calorie control diet, in transgenic mice overexpressing COX-2 [bovine keratin-5 promoter (BK5.COX-2)]. These findings in CR mice correlated with reductions in Ki-67-positive cells, vascular luminal size, VEGF expression, and phosphorylation and total expression of downstream mediators of the IGF-1 pathway. Cell lines derived from BK5.COX-2 ductal lesions (JC101 cells) formed pancreatic tumors in wild-type FVB mice that were significantly reduced in size by a 14-week CR regimen, relative to the control diet. To further understand the impact of circulating levels of IGF-1 on tumor growth in this model, we orthotopically injected JC101 cells into liver-specific IGF-1-deficient (LID) mice. The approximate 65% reduction of serum IGF-1 levels in LID mice resulted in significantly decreased burden of JC101 tumors, despite modestly elevated levels of circulating insulin and leptin. These data show that CR prevents development of dysplasia and growth of pancreatic cancer through alterations in IGF-1, suggesting that modulation of this pathway with dietary and/or pharmacologic interventions is a promising pancreatic cancer prevention strategy.
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http://dx.doi.org/10.1158/1940-6207.CAPR-11-0027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131443PMC
July 2011

Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus.

J Biol Chem 2006 Jun 10;281(23):15763-73. Epub 2006 Apr 10.

Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.

DNA (cytosine-5) methylation represents one of the most widely used mechanisms of enduring cellular memory. Stable patterns of DNA methylation are established during development, resulting in creation of persisting cellular phenotypes. There is growing evidence that the nervous system has co-opted a number of cellular mechanisms used during development to subserve the formation of long term memory. In this study, we examined the role DNA (cytosine-5) methyltransferase (DNMT) activity might play in regulating the induction of synaptic plasticity. We found that the DNA within promoters for reelin and brain-derived neurotrophic factor, genes implicated in the induction of synaptic plasticity in the adult hippocampus, exhibited rapid and dramatic changes in cytosine methylation when DNMT activity was inhibited. Moreover, zebularine and 5-aza-2-deoxycytidine, inhibitors of DNMT activity, blocked the induction of long term potentiation at Schaffer collateral synapses. Activation of protein kinase C in the hippocampus decreased reelin promoter methylation and increased DNMT3A gene expression. Interestingly, DNMT activity is required for protein kinase C-induced increases in histone H3 acetylation. Considered together, these results suggest that DNMT activity is dynamically regulated in the adult nervous system and that DNMT may play a role in regulating the induction of synaptic plasticity in the mature CNS.
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http://dx.doi.org/10.1074/jbc.M511767200DOI Listing
June 2006