Enigma of AMP-activated protein kinase subunit expression in glioma

Gliomas are the most prevalent primary brain tumors, originating from glial (non-neuronal) cells of the brain and spinal cord. Based on their aggressiveness, gliomas are classified into low-grade and high-grade tumors, with high-grade gliomas exhibiting a poor prognosis and a median survival of only 12–15 months. Autophagy is a critical cellular process that contributes to glioma development and resistance to therapy. A central regulator of autophagy and cellular energy homeostasis is AMP-activated protein kinase (AMPK), a heterotrimeric complex consisting of catalytic α, scaffolding β, and regulatory γ subunits, each with multiple isoforms. Recent evidence suggests that these AMPK subunits are differentially expressed in gliomas, contributing variably to tumor initiation, progression, and adaptation to the hypoxic and metabolically stressed tumor microenvironment. This review explores the distinctive expression patterns of AMPK subunits in glioma and their role in forming specific heterotrimeric complexes under tumor conditions. We further examine the interplay between AMPK subunits and their molecular interactors, including genetic and chemical regulators. Despite the established role of AMPK in cancer metabolism, the functional relevance of individual subunits in glioma biology remains underexplored. By highlighting emerging insights into AMPK subunit-specific functions, this review proposes that targeting unique AMPK subunit compositions may offer novel therapeutic opportunities to impede glioma progression and improve patient survival.