Peroxisome proliferation-activated receptor-gamma 1 (PPAR?) is expressed at very high levels in colonic epithelial cells. Activation of this receptor by thiazolidinedione (TZD) drugs inhibits formation of pre-neoplastic aberrant crypt foci (ACF) in pre-clinical models of sporadic colon cancer. Humans who have large numbers of ACF are at risk for colon cancer, and the pre- clinical data suggest that activation of PPAR? might reduce the burden of ACF in humans who are at risk for colon cancer. However, recent data linking TZDs to cardiovascular risk make it unlikely that any TZD will ever be used for colon cancer chemoprevention in humans. There is therefore a pressing need to figure out how to take advantage of the chemopreventive potential of PPAR? while by passing potential deleterious side effects. Our solution is to use PPAR? as a tool to identify genomic pathways that are involved in suppression of transformed growth of early stage colon cancer cells. These pathways can then be developed as chemopreventive targets downstream of PPAR?. As proof-of-concept, we have used a systems biology approach to identify calcineurin as a nodal PPAR? target that controls the activity of the NFATc family of transcription factors. PPAR? induces an endogenous calcineurin inhibitor (DSCR1), which inhibits calcineurin, leading to inhibition of NFATc activity and subsequent downregulation of key NFATc target genes involved in invasion (COX2) and proliferation (c-MYC). Calcineurin is the product of several FDA-approved drugs which we will use to test the hypothesis that calcineurin is a nodal effector of a PPAR?-regulated pathway that controls invasion and proliferation of early stage colon cancer cells (Specific Aim 1). We will determine if genetic and pharmacological inhibition of calcineurin blocks ACF formation in azoxymethane-treated mice (Specific Aim 2). Finally, we will mine our genomic data to identify other PPAR?-regulated pathways that are linked to transformation and are targets of FDA-approved drugs. These pathways will be validated and evaluated for inhibition of proliferation and/or invasion in culture, with the view of testing their chemopreventive efficacy in vivo as part of our future goals.
Project summary Humans with large numbers of pre-cancerous lesions in their colons are at increased risk for colon cancer. We have shown that activation of a gene called peroxisome proliferator-activated receptor-gamma 1 (PPAR?) blocks the formation of such lesions in mice. Unfortunately, drugs that activate PPAR? in humans may cause heart disease. So our goal is to use PPAR? as a tool to identify processes that are involved in suppressing early stages of colon cancer and then to develop these processes as therapeutic targets that can be used for colon cancer prevention without concern for the side effects of PPAR?-activating drugs.