Colorectal cancer is one of the deadliest forms of cancer and a leading cause of death in developed countries. Unfortunately, for many with chronic bowel inflammation there is a strong link between colitis and the pathogenesis of colitis associated cancer (CAC). One of the best characterized CAC contributing factors is the pro-inflammatory cytokine TNF-? and its downstream master transcription factor NF-?B. Hence, targeting the NF-?B activation pathway as a means to treat or prevent CAC progression is gaining popularity among researchers. Recently, our laboratory discovered that the bioactive sphingolipid sphingosine-1-phosphate (S1P) and the enzyme that produces it, sphingosine kinase 1 (SphK1), link persistent NF-?B activation to chronic intestinal inflammation and development of CAC. S1P and SphK1 have long been implicated in the actions of TNF-?. In the canonical TNF-dependent intracellular signaling cascade leading to NF-?B activation, a complex series of protein interactions and post-translational modifications modulate signal propagation and culminate in gene transcription. Among many others, the receptor interacting kinase-1, the TNF receptor associated factor 2 (TRAF2), and the cellular inhibitor of apoptosis 1 and 2 (cIAP1/2) play important roles. However, the molecular mechanism of the involvement of SphK1 in the NF-?B pathway has remained unclear. Importantly, both SphK1 and TRAF2 have been shown to be elevated in the tissues of patients with CAC and in the colons and tumors of animal models of the disease. My preliminary results suggest that protein-protein interactions between SphK1, TRAF2, and cIAP1/2 are important for their cellular stabilization. Hence, the hypothesis that will be examined in this proposal is that a SphK1-TRAF2-cIAP1/2 complex plays an important role in NF-?B activation by direct protein-protein interactions that regulate the stabiliy, activity and function of each protein. I also suggest that co-stabilization of the SphK1-TRAF2-cIAP1/2 complex contributes to the feed forward amplification mechanism for persistent activation of NF-?B important in chronic inflammation in colitis and development of CAC, and provides an explanation for the upregulation of SphK1 and TRAF2 in colitis and CAC. In the first aim I will elucidate the molecular mechanisms of SphK1-TRAF2-cIAP1/2 co-stabilization and examine co-regulatory effects on their respective enzymatic activities.
The second aim will investigate the function of SphK1-TRAF2-cIAP1/2 interactions in the regulation of NF-?B activation and associated biological responses. Finally, the third aim examines the cell autonomous functions of SphK1 and TRAF2 and their interactions in murine models of colitis and CAC. This proposal will provide a paradigm shift in understanding the influence of SphK1 on chronic inflammation and CAC, which has historically revolved around formation of S1P and its pleiotropic effects on cellular proliferation, protection from apoptosis, and survival, and hopefully, clarify the role of SphK1 in the etiology of chronic inflammation and CAC and provide new therapeutic strategies to interfere with upregulation of the NF-?B pathway in this deadly disease.
Unfortunately, for many with chronic bowel inflammation there is a strong link between colitis and the pathogenesis of colitis associated cancer, which is one of the deadliest forms of cancer. The bioactive lipid mediator, sphingosine-1-phosphate, and the enzyme that produces it, sphingosine kinase 1, have recently been identified as important players in the progression of colitis to colitis associated cancer. The goal of our research is to examine how sphingosine kinase 1 might affect components of the cellular signaling pathways leading to activation of the key transcription factor NF-?B, and uncover its roles in the molecular regulation processes that lead to this deadly disease.
|Lima, Santiago; Milstien, Sheldon; Spiegel, Sarah (2017) Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane Trafficking. J Biol Chem 292:3074-3088|
|Vettorazzi, Marcela; Angelina, Emilio; Lima, Santiago et al. (2017) An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors. Eur J Med Chem 139:461-481|
|Newton, Jason; Lima, Santiago; Maceyka, Michael et al. (2015) Revisiting the sphingolipid rheostat: Evolving concepts in cancer therapy. Exp Cell Res 333:195-200|