PT109, a novel multi-kinase inhibitor suppresses glioblastoma multiforme through cell reprogramming: Involvement of PTBP1/PKM1/2 pathway

Abstract

Glioblastoma multiforme (GBM) is the most prevalent type and lethal form of primary malignant brain tumor, accounting for about 40–50% of intracranial tumors and without effective treatments now. Cell reprogramming is one of the emerging treatment approaches for GBM, which can reprogram glioblastomas into non-tumor cells to achieve therapeutic effects. However, anti-GBM drugs through reprogramming can only provide limited symptom relief, and cannot completely cure GBM. Here we showed that PT109, a novel multi-kinase inhibitor, suppressed GBM's proliferation, colony formation, migration and reprogramed GBM into oligodendrocytes. Analysis of quantitative proteomics data after PT109 administration of human GBM cells showed significant influence of energy metabolism, cell cycle, and immune system processes of GBM-associated protein. Metabolomics analysis showed that PT109 improved the aerobic respiration process in glioma cells. Meanwhile, we found that PT109 could significantly increase the ratio of Pyruvate kinase M1/2 (PKM1/2) by reducing the level of polypyrimidine tract-binding protein 1 (PTBP1). Altogether, this work developed a novel anti-GBM small molecule PT109, which reprogramed GBM into oligodendrocytes and changed the metabolic pattern of GBM through the PTBP1/PKM1/2 pathway, providing a new strategy for the development of anti-glioma drugs.