FGF9 drives mitochondrial biogenesis in glioblastoma by activating the CREB-PGC-1α axis

Mitochondrial biogenesis is upregulated in glioblastoma to support tumor growth, invasion, and chemoresistance by meeting the heightened metabolic demands of cancer cells. Fibroblast growth factor 9 (FGF9) is a potent oncogenic driver in various cancers, promoting proliferation, survival, and angiogenesis. However, its role in regulating mitochondrial metabolism in glioblastoma remains unclear.

The activation of FGF9/fibroblast growth factor receptor 2 (FGFR2) signaling and expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) were examined in clinical glioblastoma samples and cell lines using real-time PCR, immunohistochemistry, and western blotting. Mitochondrial biogenesis and function in FGF9-treated U-87 cells were evaluated by measuring relative mtDNA/nDNA ratio, mitochondrial mass (MitoTracker), complex activity, membrane potential, and ATP production. The role of cAMP response element-binding protein (CREB) signaling was investigated using the specific inhibitor H89.

We found activated FGF9/FGFR2 signaling in glioblastoma patients, with elevated serum FGF9 and tumor FGFR2. PGC-1α was upregulated in samples and cell lines. FGF9 boosted mitochondrial biogenesis and function in U-87 cells, increasing mtDNA, mass, complex activity, membrane potential, and ATP production. Mechanistically, FGF9 promoted the expression of PGC-1α and mitochondrial transcription factor A (TFAM) via activation of CREB signaling. Inhibition of CREB phosphorylation by H89 abolished FGF9-induced upregulation of PGC-1α/TFAM, mtDNA replication, and ATP production.

These findings reveal that FGF9 enhances mitochondrial biogenesis in glioblastoma through the CREB-PGC-1α-TFAM axis, uncovering a novel metabolic mechanism underlying its pro-tumorigenic effects.