Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells
Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy
Department of Experimental Medicine, University of Perugia, 06126 Perugia, Italy
Laboratory of Nuclear Lipid BioPathology, CRABiON, 06122 Perugia, Italy
Dipartimento di Area Medica, University of Udine, 33100 Udine, Italy
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(11), 3424; https://doi.org/10.3390/ijms19113424
Received: 21 September 2018 / Revised: 26 October 2018 / Accepted: 29 October 2018 / Published: 1 November 2018
(This article belongs to the Special Issue Nuclear Lipid Signaling)
Daunorubicin is an anticancer drug, and cholesterol is involved in cancer progression, but their relationship has not been defined. In this study, we developed a novel experimental model that utilizes daunorubicin, cholesterol, and daunorubicin plus cholesterol in the same cells (H35) to search for the role of nuclear lipid microdomains, rich in cholesterol and sphingomyelin, in drug resistance. We find that the daunorubicin induces perturbation of nuclear lipid microdomains, localized in the inner nuclear membrane, where active chromatin is anchored. As changes of sphingomyelin species in nuclear lipid microdomains depend on neutral sphingomyelinase activity, we extended our studies to investigate whether the enzyme is modulated by daunorubicin. Indeed the drug stimulated the sphingomyelinase activity that induced reduction of saturated long chain fatty acid sphingomyelin species in nuclear lipid microdomains. Incubation of untreated-drug cells with high levels of cholesterol resulted in the inhibition of sphingomyelinase activity with increased saturated fatty acid sphingomyelin species. In daunodubicin-treated cells, incubation with cholesterol reversed the action of the drug by acting via neutral sphingomyelinase. In conclusion, we suggest that cholesterol and sphingomyelin-forming nuclear lipid microdomains are involved in the drug resistance.