Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells.
Cholesterol levels are abnormally increased in many acute myeloid leukemia (AML) samples exposed in vitro to chemotherapy. Blocking these acute cholesterol responses selectively sensitizes AML cells to therapeutics. Thus, defining the molecular mechanisms by which AML cells accomplish these protective cholesterol increments might elucidate novel therapeutic targets. We now report that the levels of mRNAs encoding the cholesterol synthesis-regulating enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and the cholesterol-importing low-density lipoprotein (LDL) receptor were both increased by daunorubicin (DNR) or cytarabine (ARA-C) treatments in almost three fourths of cultured AML samples. However, less than one third of AML samples significantly increased LDL accumulation during drug treatments, suggesting that de novo synthesis is the primary mechanism by which most AML cells increase cholesterol levels during drug exposures. LDL increments were not correlated with cholesterol increments in ARA-C-treated AML samples. However, LDL and cholesterol increments did correlate in DNR-treated AML samples where they were measured, suggesting that a subset of AMLs may rely on increased LDL accumulation during treatment with particular drugs. Our data suggest that cholesterol synthesis inhibitors may improve the efficacy of standard antileukemia regimens, but that for maximum benefit, therapy may need to be tailored for individual patients with leukemia.
Banker
Deborah E
DE
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. dbanker@fhcrc.org
Mayer
Sasha J
SJ
Li
Henry Y
HY
Willman
Cheryl L
CL
Appelbaum
Frederick R
FR
Zager
Richard A
RA
D001692:Biological Transport; D008078:Cholesterol, LDL / Q000096:biosynthesis* / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000235:genetics; D003561:Cytarabine / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D014407:Tumor Cells, Cultured
D008078:Cholesterol, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D003561:Cytarabine; C012258:mevastatin; D008148:Lovastatin; D006904:Hydroxymethylglutaryl-CoA Synthase; D003066:Coenzyme A Ligases