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Identification of Gliotoxin isolated from marine fungus as a new pyruvate kinase M2 inhibitor.

Abstract：

:Pyruvate kinase M2 (PKM2) functions as an important rate-limiting enzyme of aerobic glycolysis that is involved in tumor initiation and progression. However, there are few studies on effective PKM2 inhibitors. Gliotoxin is a marine-derived fungal secondary metabolite with multiple biological activities, including immunosuppression, cytotoxicity, and et al. In this study, we found that Gliotoxin directly bound to PKM2 and inhibited its glycolytic activity in a dose-dependent manner accompanied by the decreases in glucose consumption and lactate production in the human glioma cell line U87. Moreover, Gliotoxin suppressed tyrosine kinase activity of PKM2, leading to a dramatic reduction in Stat3 phosphorylation in U87 cells. Furthermore, Gliotoxin suppressed cell viability in U87 cells, and cytotoxicity of Gliotoxin on U87 cells was obviously augmented under hypoxia condition compared to normal condition. Finally, Gliotoxin was demonstrated to induce cell apoptosis of U87 cells and synergize with temozolomide. Our findings identify Gliotoxin as a new PKM2 inhibitor with anti-tumor activity, which lays the foundation for the development of Gliotoxin as a promising anti-tumor drug in the future.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Tang W,Liu ZL,Mai XY,Qi X,Li DH,Gu QQ,Li J

doi

10.1016/j.bbrc.2020.05.139

subject

Has Abstract

pub_date

2020-07-30 00:00:00

pages

594-600

issue

3

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(20)31067-6

journal_volume

528

pub_type

杂志文章

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