Macrophage-Associated PGK1 Phosphorylation Promotes Aerobic Glycolysis and Tumorigenesis

Abstract

Macrophages are a dominant leukocyte population in the tumor microenvironment and actively promote cancer progression. However, the molecular mechanism underlying the role of macrophages remains poorly understood. Here we show that polarized M2 macrophages enhance 3-phosphoinositide-dependent protein kinase 1 (PDPK1)-mediated phosphoglycerate kinase 1 (PGK1) threonine (T) 243 phosphorylation in tumor cells by secreting interleukin-6 (IL-6). This phosphorylation facilitates a PGK1-catalyzed reaction toward glycolysis by altering substrate affinity. Inhibition of PGK1 T243 phosphorylation or PDPK1 in tumor cells or neutralization of macrophage-derived IL-6 abrogates macrophage-promoted glycolysis, proliferation, and tumorigenesis. In addition, PGK1 T243 phosphorylation correlates with PDPK1 activation, IL-6 expression, and macrophage infiltration in human glioblastoma multiforme (GBM). Moreover, PGK1 T243 phosphorylation also correlates with malignance and prognosis of human GBM. Our findings demonstrate a novel mechanism of macrophage-promoted tumor growth by regulating tumor cell metabolism, implicating the therapeutic potential to disrupt the connection between macrophages and tumor cells by inhibiting PGK1 phosphorylation.

O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

“…PGK1 has been shown in previous studies to possess different PTMs including phosphorylation and acetylation 18,19,38 . These site-specific modifications are differentially regulated by various Fig.…”

“…PGK1 activity is mediated by different post-translational modifications. For example, phosphorylation of PGK1 at T243 and S203 positively regulates the Warburg effect and promotes the development of glioblastoma 17,18 . Acetylation at K220 inhibits PGK1 activity but is reversed by the activation of the insulin and mTOR pathway 19 .…”

Macrophage-derived SPARC Attenuates M2-mediated Pro-tumour Phenotypes

“…To generate THP-1-derived M2 macrophages (M2), THP-1 cells were treated with 150 nM phorbol 12-myristate 13-acetate (PMA, Sigma-Aldrich, MO, USA) for 24 hours to become activated macrophages (M0) and then were cultured with new media containing 20 ng/ml IL-4 and 20 ng/ml IL-13 for another 48 hours to become M2. Real-time Polymerase Chain Reaction was employed to detect the mRNA expression level of CD163, stabilin-1, IL-10, and Arg1 in M2 to verify the successful induction [4,8,24,25]. After the induction by IL-4 and IL-13, differentiated M2 cells were washed in fresh PBS and cultured in RPMI 1640 medium.…”

Tumor‐associated macrophage interleukin‐β promotes glycerol‐3‐phosphate dehydrogenase activation, glycolysis and tumorigenesis in glioma cells

“…Glycerol‐3‐phosphate dehydrogenase is a key enzyme supporting glycolysis, 12 and M2 macrophages stimulate glycolytic metabolism in glioma cells 20 . Because we determined that M2 macrophages influenced GPD2 T10 phosphorylation, we sought to determine whether the macrophage‐induced increase in glycolysis in glioma cells was dependent on phosphorylation at T10 of GPD2.…”

“…Of particular interest to our study are IL‐1β, IL‐6 and transforming growth factor β (TGFβ) because they trigger activation of PKCδ 23‐25 . Indeed, polarized M2 cells exhibit enhanced levels of IL‐1β, IL‐6 and TGFβ (and their respective downstream targets) compared to THP‐1 cells 20 …”