Obesity is a risk factor for development of cancer. The molecular mechanisms that connect diet and weight gain to cancer have not been clearly elucidated. Recently, it has been shown that obesity-mediated metabolic stresses induce molecular signaling pathways that emanate from the endoplasmic reticulum (ER). A major ER stress responsive pathway involves activation of JNK1 leading to inhibitory serine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1, insulin resistance and loss of glucose regulation. JNK1 is also activated by mediators of inflammatory stress such as TNF-alpha. The non-steroidal anti-inflammatory drug (NSAID) aspirin and its metabolite, sodium salicylate, have profound effects on cell physiology and are widely used to treat a number of diseases including inflammation and cancer. We have found that salicylates induce phosphorylation of the a-subunit of translation initiation factor eIF2 (eIF2alpha) by the stress-activated eIF2alpha kinase ER-resident kinase PERK, resulting in inhibition of protein synthesis. PERK is activated as part of the unfolded protein response of a stressed ER, leading to reduced protein synthesis and ER stress relief. However, the ER stress pathway(s) regulated by salicylates may be unconventional. We found that salicylate treatment led to Caspase-12 activation and CHOP(gadd153) induction, two events known to accompany ER stress responses. In contrast, the well-characterized mediator of ER stress, IRE-1, was not activated. Given that salicylates regulate both inflammatory and ER stress pathways and that these pathways have been implicated in glucose regulation and cancer, we propose to test the hypothesis that salicylate action modulates insulin action via a PERK-dependent pathway. Accordingly, we will determine whether salicylates affect the activity of JNK1 in wild type mice and murine models of obesity. Events downstream of JNK1 that indicate insulin signaling such as inhibitory and activating phosphorylation of IRS-1 will be examined. In addition, we will investigate the molecular pathways upstream of JNK1 to determine the relative contribution of salicylate activation of PERK as compared to salicylate inhibition of IKKbeta. The broad objective of these studies is to improve our understanding of whether salicylate treatment might be of therapeutic use in restoring insulin sensitivity and appropriate glucose regulation to ultimately prevent obesity and its health consequences.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1)
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Case Western Reserve University
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Doerner, Stephanie K; Reis, Edimara S; Leung, Elaine S et al. (2016) High-Fat Diet-Induced Complement Activation Mediates Intestinal Inflammation and Neoplasia, Independent of Obesity. Mol Cancer Res 14:953-965
Feng, Zhaoyang; Hanson, Richard W; Berger, Nathan A et al. (2016) Reprogramming of energy metabolism as a driver of aging. Oncotarget 7:15410-20
Yuan, Yiyuan; Hakimi, Parvin; Kao, Clara et al. (2016) Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans. J Biol Chem 291:1307-19
Noy, Noa; Li, Li; Abola, Matthew V et al. (2015) Is retinol binding protein 4 a link between adiposity and cancer? Horm Mol Biol Clin Investig 23:39-46
Abola, Matthew V; Thompson, Cheryl L; Chen, Zhengyi et al. (2015) Serum levels of retinol-binding protein 4 and risk of colon adenoma. Endocr Relat Cancer 22:L1-4
Spilsbury, James C; Storfer-Isser, Amy; Rosen, Carol L et al. (2015) Remission and incidence of obstructive sleep apnea from middle childhood to late adolescence. Sleep 38:23-9
Hibbs, Anna Maria; Storfer-Isser, Amy; Rosen, Carol et al. (2014) Advanced sleep phase in adolescents born preterm. Behav Sleep Med 12:412-24
Gharib, Sina A; Seiger, Ashley N; Hayes, Amanda L et al. (2014) Treatment of obstructive sleep apnea alters cancer-associated transcriptional signatures in circulating leukocytes. Sleep 37:709-14
Ochs-Balcom, Heather M; Vaughn, Caila B; Nie, Jing et al. (2014) Racial differences in the association of insulin-like growth factor pathway and colorectal adenoma risk. Cancer Causes Control 25:161-70
Boeke, Caroline E; Storfer-Isser, Amy; Redline, Susan et al. (2014) Childhood sleep duration and quality in relation to leptin concentration in two cohort studies. Sleep 37:613-20

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