title: 6-Mercaptopurine augments glucose transport activity in skeletal muscle cells in part via a mechanism dependent upon orphan nuclear receptor NR4A3.
abstract: The purine anti-metabolite 6-mercaptopurine (6-MP) is widely used for the treatment of leukemia and inflammatory diseases. The cellular effects of 6-MP on metabolism remain unknown; however, 6-MP was recently found to activate the orphan nuclear receptor NR4A3 in skeletal muscle cell lines. We have reported previously that NR4A3 (also known as NOR-1, MINOR) is a positive regulator of insulin sensitivity in adipocytes. To further explore the role of NR4A3 activation in insulin action, we explored whether 6-MP activation of NR4A3 could modulate glucose transport system activity in L6 skeletal muscle cells. We found that 6-MP increased both NR4A3 expression and NR4A3 transcriptional activity and enhanced glucose transport activity via increasing GLUT4 translocation in both basal and insulin-stimulated L6 cells in an NR4A3-dependent manner. Furthermore, 6-MP increased levels of phospho-AS160, although this effect was not modulated by NR4A3 overexpression or knockdown. These primary findings provide a novel proof of principle that 6-MP, a small molecule NR4A3 agonist, can augment glucose uptake in insulin target cells, although this occurs via both NR4A3-dependent and -independent actions; the latter is related to an increase in phospho-AS160. These results establish a novel target for development of new treatments for insulin resistance.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Qinglan
authors.initials: Q
authors.lastname: Liu
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhu
authors.forename: Lusheng
authors.initials: L
authors.lastname: Xu
authors.forename: Yuchang
authors.initials: Y
authors.lastname: Fu
authors.forename: W Timothy
authors.initials: WT
authors.lastname: Garvey
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance; D015122:Mercaptopurine / Q000494:pharmacology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013268:Stimulation, Chemical; D014178:Translocation, Genetic
chemical_list: D000963:Antimetabolites; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D051246:Glucose Transport Proteins, Facilitative; D051275:Glucose Transporter Type 4; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; D012313:RNA; D015122:Mercaptopurine; D005947:Glucose
keywords: 6-mercaptopurine; Akt substrate of 160 kDa; NR4A3; gloucose transporter 4 translocation; glucose transport; insulin action; skeletal muscle
references.citation: Am J Med. 2010 Mar;123(3 Suppl):S38-48
references.pmid: 20206731
references.citation: J Biol Chem. 2004 Dec 17;279(51):53338-45
references.pmid: 15456745
references.citation: FEBS Lett. 2008 Jan 9;582(1):2-9
references.pmid: 18023286
references.citation: N Engl J Med. 2007 Jun 14;356(24):2457-71
references.pmid: 17517853
references.citation: Med Sci Monit. 2004 Nov;10(11):RA247-54
references.pmid: 15507865
references.citation: J Clin Invest. 1998 Jun 1;101(11):2377-86
references.pmid: 9616209
references.citation: Diabetes. 2006 Jun;55(6):1776-82
references.pmid: 16731842
references.citation: N Engl J Med. 2002 Feb 7;346(6):393-403
references.pmid: 11832527
references.citation: J Biol Chem. 2003 Jul 4;278(27):24791-9
references.pmid: 12709433
references.citation: J Mol Endocrinol. 2005 Jun;34(3):835-48
references.pmid: 15956351
references.citation: Appl Physiol Nutr Metab. 2009 Jun;34(3):481-7
references.pmid: 19448718
references.citation: J Biol Chem. 2005 May 13;280(19):19250-8
references.pmid: 15716272
references.citation: J Biol Chem. 2003 Apr 25;278(17):14599-602
references.pmid: 12637568
references.citation: Endocrine. 2007 Feb;31(1):5-17
references.pmid: 17709892
references.citation: J Biol Chem. 2005 Nov 11;280(45):37803-13
references.pmid: 16154996
references.citation: Nucl Recept Signal. 2006;4:e002
references.pmid: 16604165
references.citation: Horm Metab Res. 2013 Mar;45(3):213-20
references.pmid: 23104421
references.citation: J Pediatr. 2001 Mar;138(3):428-31
references.pmid: 11241057
references.citation: Physiology (Bethesda). 2005 Aug;20:260-70
references.pmid: 16024514
references.citation: Cell. 1999 Jul 9;98(1):115-24
references.pmid: 10412986
references.citation: Physiol Rev. 1995 Jul;75(3):473-86
references.pmid: 7624391
references.citation: J Biol Chem. 2007 Oct 26;282(43):31525-33
references.pmid: 17785466
references.citation: Diabetes. 1992 Mar;41(3):274-85
references.pmid: 1372573
references.citation: Curr Opin Investig Drugs. 2009 Oct;10(10):1085-90
references.pmid: 19777397
references.citation: Am J Physiol Endocrinol Metab. 2011 Jul;301(1):E164-71
references.pmid: 21505148
references.citation: J Biol Chem. 2008 Feb 15;283(7):4228-40
references.pmid: 18079123
references.citation: Mol Cell Endocrinol. 2009 Oct 15;309(1-2):101-8
references.pmid: 19465082
references.citation: Mol Endocrinol. 2010 Oct;24(10):1891-903
references.pmid: 20392876
references.citation: FEBS Lett. 1998 May 8;427(2):193-7
references.pmid: 9607310
references.citation: J Biol Chem. 2003 Jul 4;278(27):24776-90
references.pmid: 12709428
references.citation: Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1535-41
references.pmid: 20631354
references.citation: Med Clin North Am. 2004 Jul;88(4):787-835, ix
references.pmid: 15308380
references.citation: Diabetes. 2006 Jul;55(7):2067-76
references.pmid: 16804077
references.citation: Mol Endocrinol. 2008 Aug;22(8):1743-53
references.pmid: 18258684
references.citation: Endocrinology. 2008 Jun;149(6):2853-65
references.pmid: 18325999
references.citation: Endocrinology. 2006 Nov;147(11):5217-27
references.pmid: 16901967
references.citation: Med Pediatr Oncol. 2002 Jul;39(1):32-4
references.pmid: 12116076
references.citation: J Pediatr Hematol Oncol. 2011 Mar;33(2):e75-6
references.pmid: 21343747
references.citation: Mol Endocrinol. 2012 Mar;26(3):372-84
references.pmid: 22282471
references.citation: Biochim Biophys Acta. 1996 Sep 11;1308(3):205-14
references.pmid: 8809112
references.citation: J Appl Physiol (1985). 2012 Dec 15;113(12):1852-61
references.pmid: 22936728
references.citation: Diabetes. 2007 Aug;56(8):2093-102
references.pmid: 17513702
references.citation: Am J Physiol Endocrinol Metab. 2012 Nov 15;303(10):E1273-86
references.pmid: 23011063