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Novel Mechanisms of Regulation of Bioactive Sphingolipids in Cancer Biology
Author(s) -
Obeid Lina M.,
Senkal Can,
PulkoskiGross Michael
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.527.3
Subject(s) - sphingolipid , ceramide , sphingosine , lipid signaling , sphingosine kinase , microbiology and biotechnology , biology , phosphatidic acid , kinase , signal transduction , biochemistry , cancer cell , sphingosine 1 phosphate , cancer , enzyme , apoptosis , phospholipid , membrane , genetics , receptor
Our laboratory focuses on studying the role and regulation of bioactive sphingolipids in cancer. Specifically, we are interested in metabolic pathways of ceramide ‐‐ the growth suppressor, proapoptotic, prosenescense lipid, and sphingosine‐1‐phosphate (S1P) ‐‐ the antiapoptotic, proangiogenic, promitotic lipid. Our recent studies have led us to uncover a novel metabolic pathway involving de novo ceramide acylation to lead to acylceramide generation by a protein complex of ceramide synthase (CerS), acyl‐CoA synthetase long‐chain family member 5 (ACSL5), and diglyceride acyltransferase 2 (DGAT2). This metabolic pathway leads to sequestration of acylceramide in lipid droplets thus making it unavailable for ceramide action in cell death pathways. The implications of this pathway to fatty liver and cancer will be discussed. In other recent studies, we have also uncovered a novel mechanism of regulation for the enzyme sphingosine kinase 1 by phosphatidic acid (PA) acid binding, activation and translocation to the cell membrane leading to several biologic consequences including ezrin phosphorylation and cell invasion. Moreover, this regulation of sphingosine kinase 1 appears to have implications to its role in endocytosis and other membrane structural changes. Taken all together these studies underscore the important role of bioactive sphingolipids and their metabolizing enzymes in cell regulation and cancer biology. Support or Funding Information 5I01BX000156‐0 (Obeid ‐ PI) 1.2 cal. mos. 10/1/2010 – 9/30/2017 Veteran's Administration Merit Award $258,300 “Bioactive Sphingolipid enzymes as targets in inflammation” The long‐term goal of this project is to define the role of ceramidases and sphingosine kinase in inflammation and to target these enzymes for novel anti‐inflammatory therapy. 2P01CA097132‐11A1 (Hannun – PI, Obeid ‐ Project 3 Leader) 7/01/2002‐8/31/2019 Agency: NIH/NCI 1.2 cal. mos. $133,257 Sphingolipids in Cancer Biology and Therapy The aims of this proposal are to study the role of sphingosine kinase in p53 null and mutant cancer development. 9R01GM097741‐13A1(Obeid ‐ PI) 1.2 cal. mos. 8/1/2015‐6/31/2019 Agency: NIGMS $250,000 A novel ceramide metabolic pathway in cell regulation The aim of this proposal is to study our newly discovered pathway of ceramide metabolism involving o‐acyl ceramide generation and its association with lipid droplets and regulation of cell death pathways.