A novel pyruvate kinase M2 activator compound that suppresses lung cancer cell viability under hypoxia

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme implicated in cancer cell metabolic reprogramming.
• PKM2 is a validated therapeutic target for cancer treatment due to its role in metabolic rewiring.

Purpose of the Study:

• To identify and characterize novel activators of PKM2.
• To evaluate the therapeutic potential of a newly discovered PKM2 activator, PA-12, in lung cancer.

Main Methods:

• Molecular docking-based virtual screening was employed to identify potential PKM2 activators.
• In vitro enzyme activity assays were performed using recombinant PKM2.
• Lung cancer cell proliferation assays (anchorage-dependent and -independent) were conducted.
• Nuclear translocation of PKM2 and downstream hypoxia-inducible factor 1 (HIF-1) signaling were assessed.

Main Results:

• PA-12 was identified as a novel PKM2 activator with a half-maximal activity concentration of 4.92 μM.
• PA-12 suppressed lung cancer cell growth in vitro and blocked PKM2 nuclear translocation.
• PA-12 inhibited hypoxia response element (HRE)-mediated reporter activity and HIF-1 target gene expression, reducing cell viability under hypoxia.
• The observed effects of PA-12 were dependent on PKM2 expression, confirming its specificity.

Conclusions:

• PA-12 is a potent and specific activator of PKM2.
• PA-12 demonstrates significant therapeutic potential for treating lung cancer by targeting PKM2 and associated metabolic pathways.