OP20. THE INVOLVEMENT OF CERAMIDES IN IMATINIB INDUCED APOPTOSIS AND DRUG RESISTANCE
YUSUF BARAN1,2, Ufuk Gündüz1, Can E. Senkal2, Jacek Bielawski2, Besim Öğretmen2. 1. Middle East Technical University, Department of Biology, TURKEY. 2. Medical University of South Carolina, Department of Biochemistry and Molecular Biology, USA. e-mail: ybaran@metu.edu.tr
*Corresponding Author:
page: 44

Abstract

Ceramide is intimately involved in the regulation of cancer-cell growth, differentiation, senescence and apoptosis. Ceramide seems to transduce these regulatory pathways predominantly by regulating specific protein targets such as phosphatases and kinases. These protein targets, in turn, modulate the components of various signaling pathways (AKT, phospholipase-D, PKC and MAPKs). Resistance to chemotherapeutic agents is the major reason for the failure of clinical cancer treatment. There is a mounting evidence suggesting that cells have aberrant ceramide metabolism acquire resistance to different chemotherapeutic agents. To examine whether ceramide synthesis is involved in the resistance to imatinib, an anticancer agent used for the treatment of chronic myeloid leukemia (CML), the levels of endogenous ceramides in sensitive (K562) and imatinib-resistant (K562/IMA-1) cells, in the absence or presence of imatinib, were measured by liquid chromotography/mass spectrometry. Interestingly, the data showed that treatment with imatinib resulted in a significant increase in the generation of C18-ceramide (30-fold), and to a lesser extent, C14-, C16-, and C-20-ceramides (2- to 8-fold) in K562 cells when compared to untreated controls. On the other hand, in K562/IMA-1 cells exposed to imatinib there were no significant changes in the levels of these ceramides. Indeed, further data demonstrated that expression levels hLASS1 gene which specifically generates C18-ceramide, sphingosine kinase-1 which converts pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, and glucosylceramide synthas which converts ceramide to glucosylceramide, were increased significantly in K562/IMA-1 cells. Taken together all these data suggest that intracellular concentrations of ceramide may be responsible for resistance to imatinib.




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