Abstract |
In this study, endogenous long chain ceramides were measured in 32 human head and neck squamous cell carcinoma ( HNSCC) and 10 nonsquamous head and neck carcinoma tumor tissues, as compared with adjacent noncancerous tissues, by liquid chromatography/mass spectroscopy. Interestingly, only one specific ceramide, C(18:0)- ceramide, was selectively down-regulated in the majority of HNSCC tumor tissues. On the other hand, in nonsquamous tumor tissues, this selectivity for C18-ceramide was not detected. These data suggested the hypotheses that decreased levels of C18-ceramide might impart a growth advantage to HNSCC cells and that increased generation of C18-ceramide may be involved in the inhibition of growth. These roles were examined by reconstitution of C18-ceramide at physiologically relevant concentrations in UM-SCC-22A cells (squamous cell carcinoma of hypopharynx) via overexpression of mammalian upstream regulator of growth and differentiation factor 1 (mUOG1), a mouse homologue of longevity assurance gene 1 (mLAG1), which has been shown to specifically induce the generation of C18-ceramide. Liquid chromatography/mass spectroscopy analysis showed that overexpression of the mLAG1/mUOG1 resulted in increased levels of only C(18:0)- ceramide by approximately 2-fold, i.e. concentrations similar to those of normal head and neck tissues. Importantly, increased generation of C18-ceramide by mLAG1/mUOG1 inhibited cell growth (approximately 70-80%), which mechanistically involved the modulation of telomerase activity and induction of apoptotic cell death by mitochondrial dysfunction. In conclusion, this study demonstrates, for the first time, a biological role for LAG1 and C18-ceramide in the regulation of growth of HNSCC.
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Authors | Serap Koybasi, Can E Senkal, Kamala Sundararaj, Stefka Spassieva, Jacek Bielawski, Walid Osta, Terry A Day, James C Jiang, S Michal Jazwinski, Yusuf A Hannun, Lina M Obeid, Besim Ogretmen |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 279
Issue 43
Pg. 44311-9
(Oct 22 2004)
ISSN: 0021-9258 [Print] United States |
PMID | 15317812
(Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Ceramides
- Coloring Agents
- DNA, Complementary
- LAG1 protein, S cerevisiae
- Membrane Proteins
- N-stearoylsphinganine
- Proteins
- RNA, Messenger
- Saccharomyces cerevisiae Proteins
- Tetrazolium Salts
- Thiazoles
- CERS1 protein, human
- Sphingosine N-Acyltransferase
- Telomerase
- thiazolyl blue
- Trypan Blue
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Topics |
- Animals
- Apoptosis
- Carcinoma, Squamous Cell
(drug therapy)
- Cell Division
- Cell Line, Tumor
- Ceramides
(chemistry, metabolism)
- Chromatography, Liquid
- Coloring Agents
(pharmacology)
- DNA, Complementary
(metabolism)
- Head and Neck Neoplasms
(drug therapy)
- Humans
- Mass Spectrometry
- Membrane Potentials
- Membrane Proteins
(biosynthesis)
- Mice
- Mitochondria
(metabolism)
- Proteins
(metabolism, physiology)
- RNA, Messenger
(metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Saccharomyces cerevisiae Proteins
(biosynthesis)
- Sphingosine N-Acyltransferase
- Telomerase
(metabolism)
- Tetrazolium Salts
(pharmacology)
- Thiazoles
(pharmacology)
- Trypan Blue
(pharmacology)
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