Abstract
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.
Highlights
Drug resistance is the biggest obstacle for cancer treatment
A dose-response of DNR study revealed that, by increasing the dose from 0.2 to 2 μM, the number of cells was sharply reduced for concentrations higher than 1 μM (Figure 1, Supplementary Table S1) and this concentration was used for all experiments; 800 nM CHO was chosen because it corresponds to a blood condition of hypercholesterolemia [2]
Consolidating our previous studies that hint at a role of nuclear lipid microdomains (NLM) in anchoring active chromatin and in regulating duplication and transcription processes [16,17,18,19,22,23], we demonstrate that DNR induces perturbation of NLM
Summary
Large-scale cancer drug studies provide information about the role of daunorubicin (DNR) to delay cell growth. DNR-induced apoptosis of acute lymphoblastic leukemia cells is increased by the loss of the signal transducer and activator of transcription 6 (STAT6) [4]. The focus on DNR resistance has expanded from its origin in drug regulation to multiple biological processes of cancer [8,9]. In Breast Cancer MCF-7 Cells, P-Glycoprotein is recognized to be implicated in DNR resistance [10]. High expression of the ATP-binding cassette-multi-drug efflux protein 1 confers resistance to DNR in mucosal-associated invariant T cells [11]. Altered expression of atg, HSPA1B, collagen XIII, collagen XXAI, slug, snail, and zeb genes has been related to multiple drug resistance, including DNR-resistance [12]. In a previous study we found a critical role of cholesterol (CHO) and sphingomyelin (SM) in DNR resistance [2]
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