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J. Biol. Chem., Vol. 279, Issue 43, 44311-44319, October 22, 2004

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Defects in Cell Growth Regulation by C_18:0-Ceramide and Longevity Assurance Gene 1 in Human Head and Neck Squamous Cell Carcinomas^*

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||, and Besim Ogretmen

From the Departments of Biochemistry and Molecular Biology, Otolaryngology/Head and Neck Surgery, and ^||Medicine and the Ralph H. Johnson Veterans Affairs Medical Center, Medical University of South Carolina, Charleston, South Carolina 29425, the ^**Louisiana State University Health Sciences Center, Department of Biochemistry and Molecular Biology, New Orleans, Louisiana 70112, and ^¶Abant Izzet Baysal University, Izzet Baysal Medical Faculty, Department of Otolaryngology, Bolu, Turkey

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 C -ceramide might impart a growth advantage to HNSCC ¹⁸cells 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 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 (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.

Received for publication, June 21, 2004 , and in revised form, July 26, 2004.

^* This work was supported by National Institutes of Health Grants CA-88932 (to B. O.), AG-16583 (to L. M. O.), AG06168 (to S. M. J.), and CA-097132 (to Y. A. H.) and by funds from the Department of Defense (Phase VI program project through the Hollings Cancer Center) (to B. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. E-mail: ogretmen{at}musc.edu.

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