Functional characterization of Phosphoenolpyruvate Carboxykinase 2 in Group 3 Medulloblastoma using Mass Spectrometry

ABSTRACT: Group 3 medulloblastoma (G3 MB) is an aggressive pediatric brain tumor subtype associated with poor prognosis and high metastasis, comprising about 20–25% of cases. G3 MB commonly features MYC amplification, which drives oncogenic transcription, enhanced biosynthesis, and metabolic rewiring to support rapid tumor growth. Prior proteomic studies in an Indian cohort revealed alterations in glucose and pyruvate metabolism, with notable overexpression of mitochondrial phosphoenolpyruvate carboxykinase (PCK2), an enzyme linking the TCA cycle and pyruvate metabolism that enhances metabolic adaptability under nutrient stress. This study investigated PCK2's functional role by knocking down its expression in HD-MB03 cells using shRNA. After 72 hours of doxycycline induction, proteomic analysis via the Evosep-Tims TOF platform quantified over 5000 proteins, uncovering broad proteomic changes including dysregulation of key interactors such as ENO3, LDHA, and ALDOC. Enrichment analyses revealed disruptions in gene expression, nitrogen metabolism, and RNA processing pathways, alongside increased ribosomal and ribonucleoprotein biogenesis proteins, suggesting a novel connection between PCK2 and RNA translation machinery. Metabolomic profiling showed enrichment of phosphocholines and carnitine derivatives and depletion of glutathione species, indicating impacts on lipid metabolism and redox balance. Altogether, this work elucidates PCK2's central role in regulating metabolic plasticity and ribosomal function in Group 3 MB and positions it as a promising therapeutic target to exploit the unique metabolic vulnerabilities of aggressive tumors.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Prof. Sanjeeva Srivastava 

PROVIDER: PXD070897 | JPOST Repository | Wed May 06 00:00:00 BST 2026

REPOSITORIES: jPOST