Elevation of de novo ceramide synthesis in tumor masses and the role of microsomal dihydroceramide synthase

Koyanagi Satoru, Minoru Kuga, Shinji Soeda, Yoshiko Hosoda, Tsutomu Yokomatsu, Hiroaki Takechi, Takeshi Akiyama, Shiroshi Shibuya, Hiroshi Shimeno

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Ceramide is formed through sphingomyelin hydrolysis or de novo synthesis and may play a key role in cell growth, differentiation and apoptosis. To clarify which pathway tumor cells use to form ceramide and how its formation is regulated, we determined the levels of dihydroceramide and ceramide in mice inoculated with Sarcoma 180, B16 melanoma or Lewis lung carcinoma cells. The levels in these tumor masses were very high compared to those in other healthy tissues. The high levels were significantly reduced by a single administration of the dihydroceramide synthase inhibitor fumonisin B1, but not by a sphingomyelinase inhibitor, sphingomyelin analog-1 (SMA-1), suggesting that the tumor cells have a very effective means of synthesizing dihydroceramide and ceramide. To investigate the characteristics of dihydroceramide synthase, we prepared microsomes from Sarcoma 180 tumor masses and healthy mouse liver cells, and compared their catalytic activities on dihydroceramide formation. A kinetic analysis using sphinganine and palmitoyl CoA as substrates revealed that the enzyme present in the tumor formed dihydroceramide 3 times more efficiently than that in healthy liver cells. Partial purification of dihydroceramide synthase from bovine liver microsomes revealed that the enzyme was present in healthy tissues as a 333 kDa form constructed of 47 kDa subunit proteins. However, gel filtration of the enzyme solubilized from the Sarcoma 180 tumor masses demonstrated that its molecular weight was 1,300 kDa. These results suggest that malignant transformation causes the cell to produce a form of dihydroceramide synthase with a larger than normal molecular mass; the increased molecular mass may account for the enzyme's increased catalytic efficiency.

Original languageEnglish
Pages (from-to)1-6
Number of pages6
JournalInternational Journal of Cancer
Volume105
Issue number1
DOIs
Publication statusPublished - May 20 2003
Externally publishedYes

Fingerprint

Ceramides
Sarcoma 180
Neoplasms
Sphingomyelins
Enzymes
Palmitoyl Coenzyme A
Lewis Lung Carcinoma
Sphingomyelin Phosphodiesterase
Experimental Melanomas
Liver
Protein Subunits
Liver Microsomes
Microsomes
Gel Chromatography
dihydroceramide synthase
Cell Differentiation
Hydrolysis
Molecular Weight
Apoptosis
dihydroceramide

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Elevation of de novo ceramide synthesis in tumor masses and the role of microsomal dihydroceramide synthase. / Satoru, Koyanagi; Kuga, Minoru; Soeda, Shinji; Hosoda, Yoshiko; Yokomatsu, Tsutomu; Takechi, Hiroaki; Akiyama, Takeshi; Shibuya, Shiroshi; Shimeno, Hiroshi.

In: International Journal of Cancer, Vol. 105, No. 1, 20.05.2003, p. 1-6.

Research output: Contribution to journalArticle

Satoru, K, Kuga, M, Soeda, S, Hosoda, Y, Yokomatsu, T, Takechi, H, Akiyama, T, Shibuya, S & Shimeno, H 2003, 'Elevation of de novo ceramide synthesis in tumor masses and the role of microsomal dihydroceramide synthase', International Journal of Cancer, vol. 105, no. 1, pp. 1-6. https://doi.org/10.1002/ijc.11024
Satoru, Koyanagi ; Kuga, Minoru ; Soeda, Shinji ; Hosoda, Yoshiko ; Yokomatsu, Tsutomu ; Takechi, Hiroaki ; Akiyama, Takeshi ; Shibuya, Shiroshi ; Shimeno, Hiroshi. / Elevation of de novo ceramide synthesis in tumor masses and the role of microsomal dihydroceramide synthase. In: International Journal of Cancer. 2003 ; Vol. 105, No. 1. pp. 1-6.
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