The long-term goals of this project are to define the role of sphingosine kinase 1 (SK1) as a novel and critical downstream target for the tumor suppressive action of p53, and to establish SK1 as a potential target for cancer therapy, especially in tumors with loss of or mutant p53. p53 and components its pathway have emerged as key tumor suppressors, which are disregulated in the majority of cancers. Targeting this pathway has been difficult due to the nature and function of the involved proteins. Over the last few years, we have begun to uncover a profound and novel connection between p53 and SK1. SK1 is a highly regulated enzyme that plays a critical role in regulating the levels of the bioactive sphingolipid sphingosine-1-phosphate (S1P), and in the clearance of ceramide. S1P has emerged as a tumor-promoting sphingolipid with actions on cell growth, angiogenesis and anti-inflammation whereas ceramide has emerged as a tumor suppressor lipid involved in regulation of cell senescence, apoptosis and growth arrest. Thus, SK1, by regulating the interconversion of these two critical bioactive lipids, assumes a central role in tumor biology. In the previous funding period we showed that induction of p53 results in loss of SK1. Moreover in our recently published studies, we demonstrated that this p53-induced loss of SK1 is critical for allowing p53-induced suppression of thymic lymphoma, osteosarcoma, and other cancers as evidenced in studies using the combined p53/SK1 knock-out mice. These ongoing studies provide previously unappreciated, novel and solid connections between p53, SK1, and bioactive sphingolipids, the latter mediating key effects of p53 on tumor suppression. In turn, these studies raise a number of fundamental questions as to the specific effects of p53 on SK1 and on the networks of bioactive sphingolipids: what bioactive lipid mediates what specific p53 responses, and what are the mechanisms involved? These findings have led us to the hypothesis that loss of SK1 is a key event in mediating the tumor suppressor effects of p53. Loss of p53 or its mutation results in persistence of SK1 which then allows tumor development and/or progression. This hypothesis will be investigated by pursuing the following specific aims: 1) To define the mechanisms by which p53 induces loss of SK1. 2) To define the role of bioactive sphingolipids in mediating the effects of p53 on tumor suppression. 3) To establish SK1 as a therapeutic target in p53-mutant cancers. Identifying the mechanisms by which p53 regulates SK1 will not only shed light on this exciting novel connection between the two components, but will also result in the identification of novel therapeutic targets.
The studies proposed in this project aim at defining how an enzyme of lipid (fat) metabolism regulates some key functions of cancer cells that result in the production of factors that regulate the ability of the tumor cells to migrate and invade. These factors also regulate how the host cells respond to the tumor cells. These pathways are turning out to have key functions in the regulation of cancer invasion and metastasis. Understanding these novel pathways and mechanisms not only enhances our understanding of cancer behavior, but also promises to lead us to the identification of novel targets for developing new inhibitors of cancer metastasis.
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|Carroll, Brittany L; Pulkoski-Gross, Michael J; Hannun, Yusuf A et al. (2016) CHK1 regulates NF-ÎºB signaling upon DNA damage in p53- deficient cells and associated tumor-derived microvesicles. Oncotarget 7:18159-70|
|Xu, Ruijuan; Wang, Kai; Mileva, Izolda et al. (2016) Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response. Oncotarget 7:18440-57|
|GarcÃa-Barros, MÃ³nica; Coant, Nicolas; Kawamori, Toshihiko et al. (2016) Role of neutral ceramidase in colon cancer. FASEB J 30:4159-4171|
|McCracken, A N; McMonigle, R J; Tessier, J et al. (2016) Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation. Leukemia :|
|Adada, Mohamad; Luberto, Chiara; Canals, Daniel (2016) Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases. Chem Phys Lipids 197:45-59|
|Espaillat, Mel Pilar; Kew, Richard R; Obeid, Lina M (2016) Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis. Adv Biol Regul :|
|Wang, K; Xu, R; Snider, A J et al. (2016) Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system. Cell Death Dis 7:e2124|
|Kitatani, K; Usui, T; Sriraman, S K et al. (2016) Ceramide limits phosphatidylinositol-3-kinase C2Î²-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid. Oncogene 35:2801-12|
|Wu, Song; Powers, Scott; Zhu, Wei et al. (2016) Substantial contribution of extrinsic risk factors to cancer development. Nature 529:43-7|
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