This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Itoh, M. Articles by Okazaki, T. Search for Related Content PubMed PubMed Citation Articles by Itoh, M. Articles by Okazaki, T.

Possible Role of Ceramide as an Indicator of Chemoresistance

Decrease of the Ceramide Content via Activation of Glucosylceramide Synthase and Sphingomyelin Synthase in Chemoresistant Leukemia¹

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507 [M. I., T. Ki., M. W., T. Ko., T. Y., Y. T., K. I., M. T., T. U., T. O.], and Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501 [Y. T.], Japan

We investigated the possibility of the proapoptotic lipid ceramide as an indicator of chemoresistance in leukemia. Doxorubicin (DOX) increased the ceramide level and apoptosis in drug-sensitive HL-60 cells but not in drug-resistant HL-60/ADR cells, under the condition that the uptake of DOX was not different between the two cell lines. In addition, exogenous N-acetylsphingosine (C2-ceramide) enhanced DOX-induced apoptosis in HL-60/ADR cells without affecting the expression of multidrug resistant-1 protein (MDR 1) and the uptake of DOX. A lower level of ceramide with higher activities of glucosylceramide synthase (GCS) and sphingomyelin synthase (SMS) was detected in HL-60/ADR cells than in HL-60 cells. In contrast, HL-60/GCS cells, overexpressing GCS, significantly inhibited DOX-induced ceramide increase and apoptosis. These observations suggest the involvement of ceramide regulation in drug resistance of leukemia cells. In vivo, the level of ceramide was lower in chemoresistant leukemia patients (6.4 ± 1.8 pmol/nmol phosphate; n = 14) than in chemosensitive patients (9.5 ± 2.7 pmol/nmol phosphate; n = 9), and the activities of GCS and SMS were more than 2-fold higher in chemoresistant leukemia cells than in chemosensitive cells. MDR-1 protein was faintly expressed in one of four chemoresistant patients, but Bcl-2 were clearly detected in four patients. Therefore, it is suggested that a decrease of the ceramide level via activation of GCS and SMS is associated with the chemoresistant condition in leukemia, probably in relation to Bcl-2 but not to MDR-1 expression.

This article has been cited by other articles:

				Y.-Y. Liu, J. Y. Yu, D. Yin, G. A. Patwardhan, V. Gupta, Y. Hirabayashi, W. M. Holleran, A. E. Giuliano, S. M. Jazwinski, V. Gouaze-Andersson, et al. A role for ceramide in driving cancer cell resistance to doxorubicin FASEB J, July 1, 2008; 22(7): 2541 - 2551. [Abstract] [Full Text] [PDF]

				A. Charruyer, S. M. Bell, M. Kawano, S. Douangpanya, T.-Y. Yen, B. A. Macher, K. Kumagai, K. Hanada, W. M. Holleran, and Y. Uchida Decreased Ceramide Transport Protein (CERT) Function Alters Sphingomyelin Production following UVB Irradiation J. Biol. Chem., June 13, 2008; 283(24): 16682 - 16692. [Abstract] [Full Text] [PDF]

				F. G. Tafesse, K. Huitema, M. Hermansson, S. van der Poel, J. van den Dikkenberg, A. Uphoff, P. Somerharju, and J. C. M. Holthuis Both Sphingomyelin Synthases SMS1 and SMS2 Are Required for Sphingomyelin Homeostasis and Growth in Human HeLa Cells J. Biol. Chem., June 15, 2007; 282(24): 17537 - 17547. [Abstract] [Full Text] [PDF]

				L. E. van Vlerken, Z. Duan, M. V. Seiden, and M. M. Amiji Modulation of Intracellular Ceramide Using Polymeric Nanoparticles to Overcome Multidrug Resistance in Cancer Cancer Res., May 15, 2007; 67(10): 4843 - 4850. [Abstract] [Full Text] [PDF]

				M. Noguchi, K. Kabayama, S. Uemura, B.-w. Kang, M. Saito, Y. Igarashi, and J.-i. Inokuchi Endogenously produced ganglioside GM3 endows etoposide and doxorubicin resistance by up-regulating Bcl-2 expression in 3LL Lewis lung carcinoma cells Glycobiology, July 1, 2006; 16(7): 641 - 650. [Abstract] [Full Text] [PDF]

				A. Holleman, M. L. den Boer, R. X. de Menezes, M. H. Cheok, C. Cheng, K. M. Kazemier, G. E. Janka-Schaub, U. Gobel, U. B. Graubner, W. E. Evans, et al. The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia Blood, January 15, 2006; 107(2): 769 - 776. [Abstract] [Full Text] [PDF]

				D. Pchejetski, M. Golzio, E. Bonhoure, C. Calvet, N. Doumerc, V. Garcia, C. Mazerolles, P. Rischmann, J. Teissie, B. Malavaud, et al. Sphingosine Kinase-1 as a Chemotherapy Sensor in Prostate Adenocarcinoma Cell and Mouse Models Cancer Res., December 15, 2005; 65(24): 11667 - 11675. [Abstract] [Full Text] [PDF]

				Y. Taguchi, T. Kondo, M. Watanabe, M. Miyaji, H. Umehara, Y. Kozutsumi, and T. Okazaki Interleukin-2-induced survival of natural killer (NK) cells involving phosphatidylinositol-3 kinase-dependent reduction of ceramide through acid sphingomyelinase, sphingomyelin synthase, and glucosylceramide synthase Blood, November 15, 2004; 104(10): 3285 - 3293. [Abstract] [Full Text] [PDF]

				D. Mahadevan and A. F. List Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies Blood, October 1, 2004; 104(7): 1940 - 1951. [Abstract] [Full Text] [PDF]

				Y. Uchida, M. Itoh, Y. Taguchi, S. Yamaoka, H. Umehara, S.-i. Ichikawa, Y. Hirabayashi, W. M. Holleran, and T. Okazaki Ceramide Reduction and Transcriptional Up-Regulation of Glucosylceramide Synthase through Doxorubicin-Activated Sp1 in Drug-Resistant HL-60/ADR Cells Cancer Res., September 1, 2004; 64(17): 6271 - 6279. [Abstract] [Full Text] [PDF]

				S. Yamaoka, M. Miyaji, T. Kitano, H. Umehara, and T. Okazaki Expression Cloning of a Human cDNA Restoring Sphingomyelin Synthesis and Cell Growth in Sphingomyelin Synthase-defective Lymphoid Cells J. Biol. Chem., April 30, 2004; 279(18): 18688 - 18693. [Abstract] [Full Text] [PDF]

				A. Holleman, M. L. d. Boer, K. M. Kazemier, G. E. Janka-Schaub, and R. Pieters Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia Blood, December 15, 2003; 102(13): 4541 - 4546. [Abstract] [Full Text] [PDF]