An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma.

in Clinical and translational medicine by Benedikt Sauer, Jan Kueckelhaus, Nadja I Lorenz, Süleyman Bozkurt, Dorothea Schulte, Jan-Béla Weinem, Mohaned Benzarti, Johannes Meiser, Hans Urban, Giulia Villa, Patrick N Harter, Christian Münch, Johannes Rieger, Joachim P Steinbach, Dieter Henrik Heiland, Michael W Ronellenfitsch

TLDR

  • The study investigates how glioblastoma cells can survive and grow when they don't have enough glucose to eat. The authors found that the cells can switch to using other types of nutrients, and that this switch is controlled by a protein called PGC-1α. The study also showed that PGC-1α is more likely to be found in areas of the brain tumor that aren't hypoxic (lacking oxygen). This suggests that the AMPK-PGC-1α pathway could be a target for treatment in glioblastoma.

Abstract

Glioblastoma, the most frequent primary malignant brain tumour in adults, is characterised by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumour cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose. We employed genetic approaches (stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of AMP-activated protein kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity. Moreover, a spatially resolved multiomic analysis was employed to correlate the gene expression pattern of PGC-1α with the local metabolic and genetic architecture in human glioblastoma tissue sections. A switch from glucose to alternative nutrients triggered an activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs promoting mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under nonglucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with nonhypoxic tumour niches defining a specific metabolic compartment. Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data confirms the relevance of PGC-1α especially in nonhypoxic tumour regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma. KEY POINTS/HIGHLIGHTS: AMPK activation induces PGC-1α expression in glioblastoma during nutrient scarcity. PGC-1α enables metabolic plasticity by facilitating metabolism of alternative nutrients in glioblastoma. PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas.

Overview

  • The study investigates the metabolic plasticity of glioblastoma cells in response to nutrient scarcity. The authors employed genetic approaches, pharmacological interventions, and a proteomic approach to identify the pathways necessary for metabolic plasticity. They found that AMPK activation induces PGC-1α expression, which facilitates metabolism of alternative nutrients in glioblastoma. The study also revealed that PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions, including genetic approaches, pharmacological interventions, and a proteomic approach. The authors found that AMPK activation induces PGC-1α expression, which facilitates metabolism of alternative nutrients in glioblastoma. They also found that PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas.

Implications and Future Directions

  • The study's findings suggest that the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma. The authors also identified that PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas. Future research could explore the role of the AMPK-PGC-1α axis in other types of brain tumours and investigate the potential of targeting this pathway for therapeutic purposes.
Read Full Article