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.
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