PMID- 26358205
OWN - NLM
STAT- MEDLINE
DCOM- 20160808
LR  - 20220330
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 765
DP  - 2015 Oct 15
TI  - Statin-mediated inhibition of cholesterol synthesis induces cytoprotective 
      autophagy in human leukemic cells.
PG  - 415-28
LID - S0014-2999(15)30237-5 [pii]
LID - 10.1016/j.ejphar.2015.09.004 [doi]
AB  - Statins exhibit anti-leukemic properties due to suppression of the mevalonate 
      pathway by the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase, and 
      subsequent depletion of cholesterol, farnesylpyrophosphate, and 
      geranylgeranylpyrophosphate. We investigated the role of autophagy, a controlled 
      intracellular self-digestion, in the anti-leukemic action of statins. Treatment 
      with low concentrations (</=6 microM) of statins, cholesterol depletion, and specific 
      inhibition of cholesterol synthesis and protein farnesylation or 
      geranylgeranylation, all inhibited proliferation of leukemic cell lines and 
      primary leukemic cells without inducing overt cell death. Statins and agents that 
      selectively reduce intracellular cholesterol levels, but not the inhibition of 
      protein farnesylation or geranylgeranylation, induced autophagy in leukemic 
      cells. The observed autophagic response was associated with the reduction of 
      phosphorylated Akt levels in the lipid rafts, accompanied by a decrease in the 
      activation of the main autophagy suppressor mammalian target of rapamycin (mTOR) 
      and its substrate ribosomal p70S6 kinase (p70S6K). No significant autophagy 
      induction and downregulation of mTOR/p70S6K activation were observed in normal 
      leukocytes. Autophagy suppression by bafilomycin A1 or RNA interference-mediated 
      knockdown of beclin-1 and microtubule-associated protein 1 light chain 3B induced 
      apoptotic death in statin-treated leukemic cells, an effect attenuated by the 
      addition of mevalonate or squalene, but not farnesylpyrophosphate or 
      geranylgeranylpyrophosphate. Therefore, while the inhibition of cholesterol 
      synthesis, protein farnesylation, and geranylgeranylation all contributed to 
      anti-leukemic effects of statins, the inhibition of cholesterol synthesis was 
      solely responsible for the induction of cytoprotective autophagy. These data 
      indicate that combined treatment with statins and autophagy inhibitors might be 
      potentially useful in anti-leukemic therapy.
CI  - Copyright (c) 2015 Elsevier B.V. All rights reserved.
FAU - Vilimanovich, Urosh
AU  - Vilimanovich U
AD  - Institute of Histology and Embryology, School of Medicine, University of 
      Belgrade, Visegradska 26, 11000 Belgrade, Serbia.
FAU - Bosnjak, Mihajlo
AU  - Bosnjak M
AD  - Institute of Histology and Embryology, School of Medicine, University of 
      Belgrade, Visegradska 26, 11000 Belgrade, Serbia.
FAU - Bogdanovic, Andrija
AU  - Bogdanovic A
AD  - Clinic of Hematology, Clinical Centre of Serbia, School of Medicine, University 
      of Belgrade, Belgrade, Serbia.
FAU - Markovic, Ivanka
AU  - Markovic I
AD  - Institute of Medical and Clinical Biochemistry, School of Medicine, University of 
      Belgrade, Belgrade, Serbia.
FAU - Isakovic, Aleksandra
AU  - Isakovic A
AD  - Institute of Medical and Clinical Biochemistry, School of Medicine, University of 
      Belgrade, Belgrade, Serbia.
FAU - Kravic-Stevovic, Tamara
AU  - Kravic-Stevovic T
AD  - Institute of Histology and Embryology, School of Medicine, University of 
      Belgrade, Visegradska 26, 11000 Belgrade, Serbia.
FAU - Mircic, Aleksandar
AU  - Mircic A
AD  - Institute of Histology and Embryology, School of Medicine, University of 
      Belgrade, Visegradska 26, 11000 Belgrade, Serbia.
FAU - Trajkovic, Vladimir
AU  - Trajkovic V
AD  - Institute of Microbiology and Immunology, School of Medicine, University of 
      Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia. Electronic address: 
      vtrajkovic@med.bg.ac.rs.
FAU - Bumbasirevic, Vladimir
AU  - Bumbasirevic V
AD  - Institute of Histology and Embryology, School of Medicine, University of 
      Belgrade, Visegradska 26, 11000 Belgrade, Serbia. Electronic address: 
      v_bumbasirevic@med.bg.ac.rs.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150908
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Autophagy/drug effects/*physiology
MH  - Cholesterol/*biosynthesis
MH  - Cytoprotection/drug effects/*physiology
MH  - Dose-Response Relationship, Drug
MH  - HL-60 Cells
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - K562 Cells
MH  - Leukemia/metabolism/*pathology/prevention & control
MH  - Membrane Microdomains/drug effects/metabolism/pathology
OTO - NOTNLM
OT  - Apoptosis
OT  - Atorvastatin (PubChem CID: 60823)
OT  - Autophagy
OT  - Cholesterol
OT  - FTI-227 (PubChem CID: 3005532)
OT  - Farnesylpyrophosphate (PubChem CID: 44134714)
OT  - GGTI-2133 (PubChem CID: 16078972)
OT  - Geranylgeranylpyrophosphate (PubChem CID: 44134732)
OT  - Leukemia
OT  - Lovastatin (PubChem CID: 53232)
OT  - Mevalonate (PubChem CID: 439230)
OT  - Ro 48-8071 (PubChem CID: 1949)
OT  - Simvastatin (PubChem CID: 54454)
OT  - Squalene (PubChem CID: 25244109)
OT  - Statins
EDAT- 2015/09/12 06:00
MHDA- 2016/08/09 06:00
CRDT- 2015/09/12 06:00
PHST- 2015/04/29 00:00 [received]
PHST- 2015/09/02 00:00 [revised]
PHST- 2015/09/02 00:00 [accepted]
PHST- 2015/09/12 06:00 [entrez]
PHST- 2015/09/12 06:00 [pubmed]
PHST- 2016/08/09 06:00 [medline]
AID - S0014-2999(15)30237-5 [pii]
AID - 10.1016/j.ejphar.2015.09.004 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2015 Oct 15;765:415-28. doi: 10.1016/j.ejphar.2015.09.004. Epub 
      2015 Sep 8.