The long-term objective of this proposal is to uncover mechanisms involved in the regulation of HNSCC pathogenesis and therapy. Human (dihydro)ceramide syntheses 1-6, (dh)CerS1-6, identified as yeast homologues of the longevity assurance gene 1-6 (LASS1-6) regulate the de novo generation of endogenous ceramides with specific fatty acid chain lengths;for example, whereas (dh)CerS1/LASS1 is responsible for the generation of C18-(dihydro)ceramide, (dh)CerS6/LASS6 generates C16-(dihydro)ceramide. These dihydroceramides are then desaturated to ceramides (with their distinct fatty acid chain lengths) by dihydroceramide desaturase (Des). In the cell, these two enzymatic steps (dihydroceramide synthesis and desaturation) occur in the endoplasmic reticulum (ER). Remarkably, our ongoing mechanistic studies reveal that knock down of LASS6/C16-(dihydro)ceramide induces ER stress, which then triggers mitochondrial apoptosis in HNSCC cells. In addition, treatment of HNSCC cells with known ER stress inducers, such as tunicamycin, results in a rapid degradation of LASS6 protein prior to apoptosis. More importantly, increased levels of C16-ceramide via induction of hl_ASS6 expression enhance resistance, and protect HNSCC cells from ER stress and cell death. Collectively, these data suggest a novel hypothesis that LASSS-generated C16-(dihydro)ceramide plays important roles in the regulation of ER homeostasis, such that down-regulation of this pathway mediates a significant component of the ER stress response, which then leads to apoptosis in HNSCC cells. To test this novel hypothesis, three Specific Aims are proposed: 1) Determine the roles of LASS6/C16-(dihydro)ceramide in the regulation of ER stress in HNSCC cells;2) Identify the mechanisms by which down-regulation of LASS6/C16-(dihydro)ceramide induces ER stress (or a component of the stress), and consequent apoptosis in HNSCC cells;and 3) Establish the in vivo roles and clinical relevance of LASS6/C16-(dihydro)ceramide in HNSCC pathogenesis and/or response to therapy via the regulation of ER stress. Thus, these studies will help determine the roles and mechanisms of action of LASS6/C16- (dihydro)ceramide in the regulation of ER stress in HNSCC cells. Importantly, these results have tremendous implications in unraveling the complexities of ceramide signaling and ER stress, in addition to clear therapeutic implications that will be defined in this proposal.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA097132-10
Application #
8381029
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$162,715
Indirect Cost
$31,551
Name
State University New York Stony Brook
Department
Type
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Lu, Songjian; Cai, Chunhui; Yan, Gonghong et al. (2016) Signal-Oriented Pathway Analyses Reveal a Signaling Complex as a Synthetic Lethal Target for p53 Mutations. Cancer Res 76:6785-6794
Carroll, Brittany L; Pulkoski-Gross, Michael J; Hannun, Yusuf A et al. (2016) CHK1 regulates NF-κB 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
García-Barros, Mónica; 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 C2β-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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