Elevation of serum pyruvate kinase M2 (PKM2) in IBD and its relationship to IBD indices

Almousa, Ahmed; Morris, Marc; Fowler, Sharyle; Jones, Jennifer; Alcorn, Jane

doi:10.1016/j.clinbiochem.2017.12.007

Cited by 30 publications

(13 citation statements)

References 39 publications

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“…HUVECs under diabetic environment are used as an in vitro model of diabetes and exhibits inflammation with modified gene and protein expression [24]. We found that the plasma PKM2 levels increased in patients with diabetes, which was consistent with the findings of previous studies showing elevated serum PKM2 level in some inflammatory diseases [31][32][33]. Plasma PKM2 level is associated with type 1 and type 2 diabetic nephropathy; thus, the assessment of serum PKM2 level is important [34].…”

Section: Discussionsupporting

confidence: 88%

Gene Regulatory Effect of Pyruvate Kinase M2 is Involved in Renal Inflammation in Type 2 Diabetic Nephropathy

Tang

Yang

et al. 2020

Exp Clin Endocrinol Diabetes

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Background and Aims The inflammation of glomerular endothelial cells induces and promotes the activation of macrophages and contributes to the development of diabetic nephropathy. Thus, this study aimed to investigate the gene regulatory effect and potential role of pyruvate kinase M2 (PKM2) in inflammatory response in diabetic nephropathy. Methods The plasma PKM2 levels of patients with diabetes were evaluated. Eight-week-old mice were divided into three groups (WT, db/db mice, and db/db mice treated with TEPP-46) and raised for 12 weeks. Blood and kidney samples were collected at the end of the experiment. Endothelial cells were stimulated with high glucose with or without TEPP-46. The expression of intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), phospho-PKM2, PKM2, phospho-STAT3, STAT3, nuclear factor kappa B (NF-kB), and phospho-NF-kB in vivo and in vitro were determined using Western blot. The activation of macrophages (CD68+CD86+) in the glomeruli was assessed via fluorescent double staining. Moreover, immune endothelial adhesion experiments were performed. Results The plasma PKM2 levels of patients with type 2 diabetes increased. P-PKM2 was up-regulated in vivo and in vitro. TEPP-46 decreased inflammatory cell infiltration and ICAM-1 expression in vivo and in vitro and inhibited the differentiation of macrophages to M1 cells in db/db mice with diabetic nephropathy. PKM2 regulated the phosphorylation of STAT3 and NF-kB. Furthermore, high glucose levels induced the transition from tetramer to dimer and the nuclear translocation of PKM2. Conclusion The gene regulatory effect of PKM2 is involved in renal inflammation in type 2 diabetic nephropathy by promoting the phosphorylation of STAT3 and NF-kB and the expression of intercellular adhesion molecule 1. Thus, the down-regulation of phosphorylated PKM2 may have protective effects against diabetic nephropathy by inhibiting renal inflammation.

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Section: Discussionsupporting

confidence: 88%

Gene Regulatory Effect of Pyruvate Kinase M2 is Involved in Renal Inflammation in Type 2 Diabetic Nephropathy

Tang

Yang

et al. 2020

Exp Clin Endocrinol Diabetes

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“…Among the four PK isoforms (PKL, PKR, PKM1, and PKM2), PKM2 is abundant in proliferative cells such as stem cells, tumor cells, and stromal cells in chronic inflammatory tissues such as RA joints 11 – 16 . Interestingly, PKM2 can be released into the extracellular space; PKM2 levels are elevated in the blood or feces of patients with cancer and chronic inflammatory diseases 11 , 17 , 18 . Extracellular PKM2 (exPKM2) can induce the proliferation and migration of cancer cells and promote angiogenesis via integrin β1 19 – 21 .…”

Section: Introductionmentioning

confidence: 99%

Extracellular pyruvate kinase M2 promotes osteoclastogenesis and is associated with radiographic progression in early rheumatoid arthritis

Han

Choi

Kim

et al. 2022

Sci Rep

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Extracellular PKM2 (exPKM2) levels have been reported to be increased in several cancers and inflammatory diseases, including rheumatoid arthritis (RA). This study aimed to investigate the association of circulating exPKM2 levels with radiographic progression in RA patients and the effect of exPKM2 on osteoclastogenesis. Plasma and synovial fluid exPKM2 levels were significantly elevated in RA patients. Plasma exPKM2 levels were correlated with RA disease activity and were an independent predictor for radiographic progression in RA patients with a disease duration of ≤ 12 months. CD14+ monocytes but not RA fibroblast-like synoviocytes secreted PKM2 upon stimulation with inflammatory mediators. Recombinant PKM2 (rPKM2) increased the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells and resorption pit in osteoclast precursors, dose-dependently, even in the absence of receptor activator of nuclear factor-kappa B ligand (RANKL). rPKM2 treatment upregulated the expression of dendrocyte-expressed seven transmembrane protein (DC-STAMP) and MMP-9 via the ERK pathway. Although rPKM2 did not directly bind to RAW264.7 cells, extracellular application of pyruvate, the end-product of PKM2, showed effects similar to those seen in rPKM2-induced osteoclastogenesis. These results suggest that exPKM2 is a potential regulator of RA-related joint damage and a novel biomarker for subsequent radiographic progression in patients with early-stage RA.

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“…TMA and IHC were performed as previously described 9 , 19 for patients who underwent surgery for primary BC between 1993 and 1998 at Asan Medical Center, Seoul, Korea. NONO antibody was used for TMA (1:200 dilution; Bethyl #A300-582A; Montgomery, TX, US).…”

Section: Methodsmentioning

confidence: 99%

RNA-binding protein NONO contributes to cancer cell growth and confers drug resistance as a theranostic target in TNBC

Kim

Kang

et al. 2020

Theranostics

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Breast cancer (BC) is one of the most common cancers in women. TNBC (Triple-negative breast cancer) has limited treatment options and still lacks viable molecular targets, leading to poor outcomes. Recently, RNA-binding proteins (RBPs) have been shown to play crucial roles in human cancers, including BC, by modulating a number of oncogenic phenotypes. This suggests that RBPs represent potential molecular targets for BC therapy. Methods: We employed genomic data to identify RBPs specifically expressed in TNBC. NONO was silenced in TNBC cell lines to examine cell growth, colony formation, invasion, and migration. Gene expression profiles in NONO-silenced cells were generated and analyzed. A high-throughput screening for NONO-targeted drugs was performed using an FDA-approved library. Results: We found that the NONO RBP is highly expressed in TNBC and is associated with poor patient outcomes. NONO binds to STAT3 mRNA, increasing STAT3 mRNA levels in TNBC. Surprisingly, NONO directly interacts with STAT3 protein increasing its stability and transcriptional activity, thus contributing to its oncogenic function. Importantly, high-throughput drug screening revealed that auranofin is a potential NONO inhibitor and inhibits cell growth in TNBC. Conclusions: NONO is an RBP upstream regulator of both STAT3 RNA and protein levels and function. It represents an important and clinically relevant promoter of growth and resistance of TNBCs. NONO is also therefore a potential therapeutic target in TNBC.

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Elevation of serum pyruvate kinase M2 (PKM2) in IBD and its relationship to IBD indices

Cited by 30 publications

References 39 publications

Gene Regulatory Effect of Pyruvate Kinase M2 is Involved in Renal Inflammation in Type 2 Diabetic Nephropathy

Gene Regulatory Effect of Pyruvate Kinase M2 is Involved in Renal Inflammation in Type 2 Diabetic Nephropathy

Extracellular pyruvate kinase M2 promotes osteoclastogenesis and is associated with radiographic progression in early rheumatoid arthritis

RNA-binding protein NONO contributes to cancer cell growth and confers drug resistance as a theranostic target in TNBC

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