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.

Severe recurrent nocturnal hypoglycemia during chemotherapy with 6-mercaptopurine in a child with acute lymphoblastic leukemia

“…Decreased gluconeogenic substrate was described as the main mechanism of hypoglycemia. Liu et al [9] confirmed that 6-MP activates nuclear receptor subfamily 4, group A, member 3, resulting in increased glucose transport and glucose transporter type 4 translocation into the basal muscle cell. This mechanism may increase skeletal muscle glucose uptake, and hypoglycemia may occur regardless of the insulin level.…”

Role of AMPK signalling pathway during compensatory growth in pigs

“…Among the set of genes under-expressed in RE animals, it is worthy to highlight the Nuclear Receptor Subfamily 4 Group A Member 3 ( NR4A3 ; FC = 2.44, P -value = 1.03 × 10 − 5 ) and 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 2 ( PFKFB2 ; FC = 2.19, P -value = 2.85 × 10 − 7 ) genes. The NR4A3 gene regulates the translocation of the SLC2A4 glucose transporter (also called GLUT4) to the surface of skeletal muscle cells to increase the uptake of glucose [ 25 ], while PFKFB2 catalyses the synthesis of fructose-2, 6-bisphosphate, a key regulator of glycolysis [ 26 ].…”

6-mercaptopurine promotes energetic failure in proliferating T cells

“…6-MP induces stabilization of HIF-1α in the HepG2 hepatocarcinoma cell line [ 21 ], whereas 6-MP decreases HIF-1α protein expression in our model. Regarding glucose uptake, in the L6 model of rat skeletal muscle, 6-MP increases glucose uptake and Glut4 (SLC2A4, solute carrier family 2, member 4) translocation to the cell surface, a process mediated by NR4A3 [ 42 ]. The fact that T cells do not express Glut4 [ 37 ] may explain why 6-MP does not promote increased glucose uptake in our model.…”