Sphingolipid metabolic enzymes modulate anticancer drug resistance
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Resistance to anticancer drugs is still a big obstacle for effective chemotherapy.To understand the underlying mechanisms, we generated sphingosine-1-phosphate (S-1-P)lyase (SPL) and sphingosine kinase (SK) mutants. Our data showed that using genetic or pharmacological methods to modulate S-1-P metabolic enzymes alters the cellular response to platinum based anticancer drugs. Moreover, we found that SPL regulates cisplatin sensitivity through p38 MAPK pathway. Furthermore, we found that overexpressing the LASS genes, which function in generating ceramide, differentially modulates sensitivity to anticancer drugs in HEK293 cells. LASS1 increased sensitivity to all tested drugs, LASS5 increase sensitivity only to drugs acting as substrates of MDR and LASS4 does not change sensitivity to any of the tested drug. We also showed that LASS1 translocates from the ER to the Golgi upon a variety of stress stimuli. Our findings, for the first time, directly connected the sphingolipid metabolic pathway with the clinical problem of anticancer drug resistance and may provide multiple potential targets for cancer treatment.
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