Alterations of Ceramide/Sphingosine 1-Phosphate Rheostat Involved in the Regulation of Resistance to Imatinib-induced Apoptosis in K562 Human Chronic Myeloid Leukemia Cells*

By Y. Baran, Arelis Salas, C. Senkal, U. Gunduz, J. Bielawski, LM Obeid, B. Ogretmen. 2007

232 citations recorded by the source corpus.

In this study, mechanisms of resistance to imatinib-induced apoptosis in human K562 cells were examined. Continuous exposure to stepwise increasing concentrations of imatinib resulted in the selection of K562/IMA-0.2 and -1 cells, which expressed ∼2.3- and 19-fold resistance, respectively. Measurement of endogenous ceramides by high performance liquid chromatography/mass spectroscopy showed that treatment with imatinib increased the generation of ceramide, mainly C18-ceramide, which is generated by the human longevity assurance gene 1 (hLASS1), in sensitive, but not in resistant cells. Inhibition of hLASS1 by small interfering RNA partially prevented imatinib-induced cell death in sensitive cells. In reciprocal experiments, overexpression of hLASS1, and not hLASS6, in drug-resistant cells caused a marked increase in imatinib-induced C18-ceramide generation, and enhanced apoptosis. Interestingly, there were no defects in the levels of mRNA and enzyme activity levels of hLASS1 for ceramide generation in K562/IMA-1 cells. However, expression levels of sphingosine kinase-1 (SK1) and generation of sphingosine 1-phosphate (S1P) were increased significantly in K562/IMA-1 cells, channeling sphingoid bases to the sphingosine kinase pathway. The partial inhibition of SK1 expression by small interference RNA modulated S1P levels and increased sensitivity to imatinib-induced apoptosis in resistant cells. On the other hand, forced expression of SK1 in K562 cells increased the ratio between total S1P/C18-ceramide levels ∼6-fold and prevented apoptosis significantly in response to imatinib. Additional data indicated a role for SK1/S1P signaling in the up-regulation of the Bcr-Abl expression at the post-transcriptional level, which suggested a possible mechanism for resistance to imatinib-mediated apoptosis. In conclusion, these data suggest a role for endogenous C18-ceramide synthesis mainly via hLASS1 in imatinib-induced apoptosis in sensitive cells, whereas in resistant cells, alterations of the balance between the levels of ceramide and S1P by overexpression of SK1 result in resistance to imatinib-induced apoptosis.

Subfields: Hematology, Molecular Biology

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Citations in the corpus

Mammalian Ceramide Synthases (2010, background): “The opposing functions that ceramide and S1P play in signaling pathways suggests that this mode of regulation might be of significance in cell physiology, and may provide a molecular explanation for the so-called ceramide/S1P rheostat (53), which proposes that the balance between S1P and ceramide de”
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): “It is well documented that increased generation of S1P by sphingosine kinase 1 (SK1) plays important roles in malignant transformation, alteration of ceramide-induced apoptosis, altered autophagy, and drug resistance [49-51].”
CERAMIDE SYNTHASE 1 IS REGULATED BY PROTEASOMAL MEDIATED TURNOVER (2009, background): “CerS1 is phylogenetically distinct, lacks a HOX-like domain [5], preferentially uses C18 acyl CoA as a substrate [13], is expressed (mRNA) most abundantly in the brain and heart [10], increases sensitivity to specific chemotherapeutic agents [17,20], and is associated with the alteration of C18 cera”
Stress-induced ER to Golgi translocation of ceramide synthase 1 is dependent on proteasomal processing (2009, unknown): “The CerS enzymes are important regulators of ceramide homeostasis, and CerS1 is central to regulating C18 ceramide, which has been shown to be important in cancer and the response to chemotherapeutic drugs [1,15,16,18].”
Roles of bioactive sphingolipids in cancer biology and therapeutics. (2008, background): “Importantly, down-regulation of SK1 significantly reversed resistance to drug-induced apoptosis in these cells (Baran et al., 2007).”