Titolo: Inhibition of cholesterol esterification increases cholesterol ester uptake from HDL in parental and MDR1 resistant CCRF-CEM cells
Data di pubblicazione: 2014
Abstract: Objectives: Cholesteryl ester (CE) content is elevated in cancer cells, while tumour bearing subjects show low levels of HDL. We have previously demonstrated that cancer cells also acquire CEs from HDL (1, 2). In the present study we further investigated this aspect in a lymphoblastic CCRFCEM cell line Methods: As multidrug-resistant P-glycoprotein-MDR1 has been involved in CE metabolism (3), CEM were made resistant by stepwise exposure to low (LR, 50nM) and high (HR, 500nM) doses of vincristine. We evaluated: P-gp activity (3H-vinblastine), CE content (HPLC), CE synthesis (14C-oleate), neutral lipid and Dil-HDL uptake (fluorescence), ACAT and SR-B1 protein expression (western blotting). The ACAT inhibitor Sandoz-58035 (SZ, 4mM), progesterone (PG, 20mM), the P-gp inhibitors cyclosporine (CLS, 2,5mM) and verapamil (VPM, 10mM), were used as inhibitors of CE synthesis. Results: CE content in LR was similar to parental, whereas it was significantly higher in HR cells. However, CE synthesis and the ACAT protein expression were similar in all groups. SZ completely inhibited CE synthesis but not proliferation and P-gp activity. PG blocked CE synthesis and proliferation but failed to revert MDR-resistance. CLS and VPM reversed MDRresistance, inhibited CE synthesis and proliferation in LR, but were highly toxic in HR cells. A higher content of neutral lipids was found in presence of all inhibitors. Except for SZ, the drugs leaded to a higher CE content, CEHDL uptake and SR-B1 protein expression then the respective controls. These effects were more evident in MDR cells. Conclusion: Our data suggest that HDL, rather than removing, may supply via SR-B1 the increase requirements of CEs in cancer cells. CE uptake is even increased when CE endogenous synthesis is inhibited, making HDL a promising tool for delivering antitumor drugs.
Tipologia:1.5 Abstract in rivista

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