title: Platelets promote mitochondrial uncoupling and resistance to apoptosis in leukemia cells: a novel paradigm for the bone marrow microenvironment.
abstract: Here we report that leukemia cell lines and primary CD34+ leukemic blasts exposed to platelet rich plasma (PRP) or platelet lysates (PL) display increased resistance to apoptosis induced by mitochondria-targeted agents ABT-737 and CDDO-Me. Intriguingly, leukemia cells exposed to platelet components demonstrate a reduction in mitochondrial membrane potential (ΔΨM) and a transient increase in oxygen consumption, suggestive of mitochondrial uncoupling. Accompanying the ranolazine-sensitive increase in oxygen consumption, a reduction in triglyceride content was also observed in leukemia cells cultured with platelet components indicating that lipolysis and fatty acid oxidation may support the molecular reduction of oxygen in these cells. Mechanistically, platelet components antagonized Bax oligomerization in accordance with previous observations supporting an antiapoptotic role for fatty acid oxidation in leukemia cells. Lastly, substantiating the notion that mitochondrial uncoupling reduces oxidative stress, platelet components induced a marked decrease in basal and rotenone-induced superoxide levels in leukemia cells. Taken together, the decrease in ΔΨM, the transient increase in ranolazine-sensitive oxygen consumption, the reduction in triglyceride levels, and the reduced generation of superoxide, all accompanying the increased resistance to mitochondrial apoptosis, substantiate the hypothesis that platelets may contribute to the chemoprotective sanctuary of the bone marrow microenvironment via promotion of mitochondrial uncoupling.
authors.affiliation: Grupo de Terapia Celular y Molecular, Pontificia Universidad Javeriana, Bogotá, Colombia.
authors.forename: Juliana
authors.initials: J
authors.lastname: Velez
authors.forename: Leonardo José
authors.initials: LJ
authors.lastname: Enciso
authors.forename: Marta
authors.initials: M
authors.lastname: Suarez
authors.forename: Michael
authors.initials: M
authors.lastname: Fiegl
authors.forename: Adriana
authors.initials: A
authors.lastname: Grismaldo
authors.forename: Catalina
authors.initials: C
authors.lastname: López
authors.forename: Alfonso
authors.initials: A
authors.lastname: Barreto
authors.forename: Claudia
authors.initials: C
authors.lastname: Cardozo
authors.forename: Pilar
authors.initials: P
authors.lastname: Palacios
authors.forename: Ludis
authors.initials: L
authors.lastname: Morales
authors.forename: Jorge Eduardo
authors.initials: JE
authors.lastname: Duque
authors.forename: Jorge Uriel
authors.initials: JU
authors.lastname: Carmona
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Ismael
authors.initials: I
authors.lastname: Samudio
references.citation: Biochem Biophys Res Commun. 1993 Nov 30;197(1):40-5
references.pmid: 8250945
references.citation: Pediatr Blood Cancer. 2011 Oct;57(4):641-7
references.pmid: 21826780
references.citation: Cancer Res. 2008 Jul 1;68(13):5198-205
references.pmid: 18593920
references.citation: Platelets. 1998;9(6):352-8
references.pmid: 16793718
references.citation: Am J Sports Med. 2011 Apr;39(4):729-34
references.pmid: 21398575
references.citation: Oncogene. 2006 May 25;25(22):3113-22
references.pmid: 16407823
references.citation: Biochemistry. 2008 Nov 25;47(47):12626-34
references.pmid: 18973303
references.citation: PLoS One. 2011 Jan 17;6(1):e14526
references.pmid: 21264222
references.citation: FEBS Lett. 2009 Jan 22;583(2):350-6
references.pmid: 19101552
references.citation: Thromb Haemost. 2008 Jan;99(1):27-37
references.pmid: 18217131
references.citation: J Biol Chem. 2000 Jul 7;275(27):20374-81
references.pmid: 10877842
references.citation: Hematology. 2011 Mar;16(2):67-72
references.pmid: 21418735
references.citation: Res Vet Sci. 2006 Oct;81(2):237-45
references.pmid: 16969921
references.citation: Oncogene. 2001 Oct 18;20(47):6840-50
references.pmid: 11687963
references.citation: J Lab Clin Med. 1983 Dec;102(6):973-86
references.pmid: 6644158
references.citation: Platelets. 2008 Mar;19(2):155-9
references.pmid: 18297552
references.citation: Cancer Res. 2011 Mar 1;71(5):1540-9
references.pmid: 21212409
references.citation: J Immunol. 2001 Jul 15;167(2):623-7
references.pmid: 11441062
references.citation: Am J Hematol. 2013 Apr;88(4):318-27
references.pmid: 23526416
references.citation: FASEB J. 2008 Jan;22(1):9-18
references.pmid: 17855623
references.citation: Mol Pharmacol. 2006 Apr;69(4):1182-93
references.pmid: 16410408
references.citation: Biomed Mater Eng. 2008;18(1 Suppl):S71-6
references.pmid: 18334717
references.citation: J Biol Chem. 2010 Jul 16;285(29):21961-8
references.pmid: 20466728
references.citation: Blood. 2011 Aug 4;118(5):1359-69
references.pmid: 21680800
references.citation: Peptides. 2008 Jan;29(1):7-14
references.pmid: 18063441
references.citation: Blood Rev. 2011 May;25(3):113-22
references.pmid: 21316823
references.citation: Cancer Res. 2009 Mar 15;69(6):2163-6
references.pmid: 19258498
references.citation: Cancer Cell. 2006 Nov;10(5):375-88
references.pmid: 17097560
references.citation: Exp Hematol. 1999 Apr;27(4):605-14
references.pmid: 10210318
references.citation: Int J Cancer. 2002 Jan 1;97(1):106-14
references.pmid: 11774251
references.citation: Biomed Mater Eng. 2009;19(4-5):271-6
references.pmid: 20042793
references.citation: Diabetes Obes Metab. 2003 Sep;5(5):295-301
references.pmid: 12940866
references.citation: Platelets. 1997;8(6):397-404
references.pmid: 16793674
references.citation: Blood. 2004 Mar 1;103(5):1815-22
references.pmid: 14630813
references.citation: Infect Immun. 2002 Dec;70(12):6524-33
references.pmid: 12438321
references.citation: J Clin Invest. 2010 Jan;120(1):142-56
references.pmid: 20038799
references.citation: J Cell Biol. 2010 Dec 27;191(7):1367-80
references.pmid: 21173115
references.citation: Cell Growth Differ. 2002 Sep;13(9):449-55
references.pmid: 12354754
references.citation: Science. 2007 Sep 21;317(5845):1767-70
references.pmid: 17885137
references.citation: J Neurooncol. 2011 Oct;105(1):45-56
references.pmid: 21384216
references.citation: Cell Death Differ. 2012 Mar;19(3):416-27
references.pmid: 21818119
references.citation: Drug Resist Updat. 2009 Aug-Oct;12(4-5):103-13
references.pmid: 19632887