Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• PKM2 regulates aerobic glycolysis and cancer cell metabolic reprogramming.
• Trib2 is generally considered a pseudokinase involved in various cancers, but its role in cancer metabolism via PKM2 is unclear.

Purpose of the Study:

• To elucidate the role of Trib2 in regulating cancer metabolism through PKM2.
• To investigate the kinase activity of Trib2 and its mechanism in cancer.

Main Methods:

• In vitro studies involving cancer cell cultures with Trib2 or PKM2 overexpression.
• In vivo experiments using Trib2 knockout (TRIB2-/-) mice.
• Analysis of PKM2 phosphorylation, nuclear translocation, gene expression (LDHA, GLUT1, PTBP1), glucose uptake, lactate production, and ATP content.

Main Results:

• Trib2 exhibits kinase activity, directly phosphorylating PKM2 at serine 37.
• Phosphorylated PKM2 (pSer37-PKM2) promotes nuclear entry, increasing LDHA, GLUT1, and PTBP1 expression.
• Elevated aerobic glycolysis, glucose uptake, and lactate production were observed in Trib2- or PKM2-overexpressed cells, leading to increased cancer cell proliferation and migration.
• TRIB2-/- mice experiments confirmed Trib2's regulation of aerobic glycolysis via PKM2.

Conclusions:

• Trib2 possesses kinase activity and phosphorylates PKM2, impacting cancer cell metabolism.
• This mechanism promotes lung cancer cell proliferation in vitro and in vivo.
• Targeting Trib2's kinase activity offers a potential therapeutic strategy for cancer by modulating cancer metabolism.