HGF/c-Met Signaling induces Glutamine Metabolism in Head and Neck Squamous Cell Carcinoma via MAPK/ERK-Dependent Induction of GLS-1

Background Head and neck squamous cell carcinoma (HNSCC) is a common malignancy characterized by poor survival due to recurrence, metastasis and therapy resistance. In addition to genetic alterations, metabolic reprogramming is a hallmark of HNSCC and contributes to tumor progression and treatment failure. The hepatocyte growth factor (HGF)/c-Met signaling pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), where it promotes tumor cell proliferation, invasion, and increased glucose metabolism. However, its contribution to the regulation of glutamine metabolism in HNSCC remains largely unexplored. Methods Human HNSCC cell lines (FaDu, SCC-154, and Detroit562) were stimulated with HGF. Expression of glutaminase 1 (GLS-1) was analyzed by quantitative PCR and Western blotting. The functional relevance of GLS-1 was evaluated by pharmacological inhibition and genetic silencing using siRNA. Cell viability and migratory capacity were assessed by wound-healing assays. Results HGF stimulation induced a pronounced increase in GLS-1 expression in HNSCC cell lines, as confirmed by qPCR and Western blotting. To elucidate the signaling mechanisms underlying this regulation, we next analyzed major c-Met downstream pathways. HGF treatment led to strong ERK1/2 phosphorylation. Pharmacological inhibition of c-Met with Foretinib or blockade of MEK1/2 with U0126 abolished ERK1/2 phosphorylation and prevented the HGF-induced upregulation of GLS-1 protein levels. These results demonstrate that HGF/c-Met–driven GLS-1 expression is mediated through activation of the MAPK/ERK pathway. Moreover, GLS-1 silencing by siRNA significantly impaired wound closure, indicating reduced proliferative and migratory capacity. Conclusion Our findings show that HGF/c-Met signaling activates the MAPK/ERK pathway to induce GLS-1 expression, thereby promoting glutamine metabolism and tumor cell motility in HNSCC. Consequently, targeting glutaminase or ERK signaling may represent a promising therapeutic approach to counteract HGF/c-Met–driven metabolic reprogramming and therapy resistance in HNSCC.