The role of dsRNA-dependent protein kinase (PKR) on colon tumor development in obese mice

Abstract

Even though obesity is recognized as an important cause of diabetes and cardiovascular disease, the association between obesity and different types of cancer is not well studied. The association between obesity and colon cancer development is a major knowledge gain in the pathogenesis of colon cancer. Recently the role of obesity-related inflammation in carcinogenesis has been better defined. It is believed that obesity acts as a tumor promoter, and its pro-tumorigenic effects depend mainly on obesity-related low-grade inflammatory response, which involves the production of inflammatory and pro-tumorigenic cytokines (TNF and IL-6). A key feature of obesity-induced inflammation is macrophage infiltration in adipose tissue, this leads to production of inflammatory cytokines and other mediators that interfere with insulin signaling pathway. Endoplasmatic reticulum (ER) stress and inflammation are connected at various levels and, as adaptive systems, its expression are necessary and beneficial only for a short period of time for the proper function and consequent survival of the organism, and although, when chronically activated they are detrimental. Thus, the activation of PKR during inflammation and ER stress and the subsequent activation of JNK by PKR also interfere with and impair the insulin signaling pathway. In this manner, PKR may form a metabolically active protein complex - called inflamasome or metaflamasome - that integrates insulin action, pathogen response, control of translation with nutrient sensitivity and ER stress. The formation of a metaflamosome and its activation by nutrients and ER stress may explain the functional overlap between multiple signaling pathways such as JNK, IKK and others in the modulation of metabolism. The relationship between colon cancer and obesity may be due to the action, at the molecular level, of the low-grade subclinical inflammation and cellular stress caused by such inflammatory signaling. Since PKR is responsive to inflammatory and insulin signaling in other tissues, and is also related to carcinogenesis and tumor progression in several types of cancer, the investigation of their role is relevant to provide an understanding of the molecular physiopathology of colon tumors. Thus, the main purpose of the study will be the evaluation of the role of PKR in the development of colon tumors in mice subjected to high fat diet. (AU)