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.

Public Health Relevance

This work is focused on determining the role of a lipid metabolizing enzyme sphingosine kinase 1 and its product sphingosine 1-phosphate in cancer growth. We will focus on a p53 mutant mouse model of cancer and try to inhibit cancer growth by inhibiting sphingosine kinase activity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA097132-11A1
Application #
8742661
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2002-07-01
Project End
2019-08-31
Budget Start
2014-09-22
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
$208,047
Indirect Cost
$74,790
Name
State University New York Stony Brook
Department
Type
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Chen, Jennifer Y; Newcomb, Benjamin; Zhou, Chan et al. (2017) Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells. Sci Rep 7:44867
Janecke, Andreas R; Xu, Ruijuan; Steichen-Gersdorf, Elisabeth et al. (2017) Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications. Hum Mutat 38:365-372
Xu, Ruijuan; Garcia-Barros, Monica; Wen, Sally et al. (2017) Tumor suppressor p53 links ceramide metabolism to DNA damage response through alkaline ceramidase 2. Cell Death Differ :
Espaillat, Mel Pilar; Kew, Richard R; Obeid, Lina M (2017) Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis. Adv Biol Regul 63:140-155
McCracken, A N; McMonigle, R J; Tessier, J et al. (2017) Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation. Leukemia 31:669-677
Pulkoski-Gross, Michael J; Uys, Joachim D; Orr-Gandy, K Alexa et al. (2017) Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis. Prostaglandins Other Lipid Mediat 130:47-56
Coant, Nicolas; Sakamoto, Wataru; Mao, Cungui et al. (2017) Ceramidases, roles in sphingolipid metabolism and in health and disease. Adv Biol Regul 63:122-131
Hernández-Corbacho, María José; Salama, Mohamed F; Canals, Daniel et al. (2017) Sphingolipids in mitochondria. Biochim Biophys Acta 1862:56-68
Bai, Aiping; Mao, Cungui; Jenkins, Russell W et al. (2017) Anticancer actions of lysosomally targeted inhibitor, LCL521, of acid ceramidase. PLoS One 12:e0177805
Lin, Chih-Li; Xu, Ruijuan; Yi, Jae Kyo et al. (2017) Alkaline Ceramidase 1 Protects Mice from Premature Hair Loss by Maintaining the Homeostasis of Hair Follicle Stem Cells. Stem Cell Reports 9:1488-1500

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