Defects in Cell Growth Regulation by C18:0-Ceramide and Longevity Assurance Gene 1 in Human Head and Neck Squamous Cell Carcinomas*

By S. Koybasi, C. Senkal, Kamala Sundararaj, Stefka D. Spassieva, J. Bielawski, Walid A. Osta, Terry A. Day, J. Jiang, S. Jazwinski, Y. A. Hannun and 2 more. 2004

231 citations recorded by the source corpus.

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, C18:0-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 C18:0-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.

Subfields: Molecular Biology, Neurology

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Markus R. Wenk

Citations in the corpus

Mammalian Ceramide Synthases (2010, background): “Moreover, the balance between levels of C16- and C18-ceramide may be related to the development of HNSCC tumor tissue (39, 40), which is also associated with the state of clinical progression of HNSCC (41).”
Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas (2007, methodology): “A role of LASS1 and C18-ceramide in the inhibition of HNSCC tumor growth and/or cell death was defined previously (20).”
Antiapoptotic roles of ceramide‐synthase‐6‐generated C16‐ceramide via selective regulation of the ATF6/ CHOP arm of ER‐stress‐response pathways (2010, methodology): “Our previous studies (3, 27, 28) have suggested that de novo-generated C18- and C16-ceramides play distinct roles in the regulation of cell death and/or the pathogenesis of HNSCCs.”
(Dihydro)ceramide Synthase 1–Regulated Sensitivity to Cisplatin Is Associated with the Activation of p38 Mitogen-Activated Protein Kinase and Is Abrogated by Sphingosine Kinase 1 (2007, background): “Head and neck cancer cells, but not normal cells, have been shown to down-regulate C18 ceramide while elevating the levels of ceramides with other fatty acyl chain lengths (26).”
The emerging field of lipidomics (2005, background): “Only some molecular species of ceramides were shown to be associated with certain types of cancers or with pathways that lead to ceramide-induced apoptosi”
CERAMIDE SYNTHASE 1 IS REGULATED BY PROTEASOMAL MEDIATED TURNOVER (2009, background): “It should be noted that CerS1 is also expressed in head and neck carcinoma cells [18,19].”
Potentiation of cannabinoid-induced cytotoxicity in Mantle Cell Lymphoma through modulation of ceramide metabolism (2009, background): “When ceramide species C18 was specifically induced in UM-SCC-22A cells (squamous cell carcinoma of hypopharynx) by overexpression of CerS1, cell growth was inhibited (6).”
Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): attenuation of C(18)-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis. (2007, background): “Thus, these data suggest that attenuation of C18-ceramide, which is known to mediate antiproliferative functions [20,21], in HNSCC tissues may play a role in the pathogenesis and/or progression of this disease.”