C-terminal interleukin 1 alpha (IL-1α) overexpression drives EMT and a vulnerability to ferroptosis in HNSCC.

High tumor expression of the cytokine interleukin-1 alpha (IL-1α) is associated with an aggressive tumor phenotype and poor clinical outcomes in head and neck squamous cell carcinoma (HNSCC). However, the mechanism behind IL-1α-induced tumor aggressiveness is unclear. The goal of this work is to investigate the biological consequences of increased IL-1α in HNSCC cells. Three IL1A constructs (Full-length, N-terminal, and C-terminal [CT]) were transduced into Cal27 HNSCC cells and validated for IL-1α expression. Differences in cell survival, metabolic profiling, epithelial-to-mesenchymal transition (EMT), oxidative stress parameters and response to therapy were compared among the parental and IL-1α overexpressing cell lines. Overexpression of CT IL-1α (but not the other constructs) led to increased cell proliferation, membrane fluidity, hydroperoxide production, intracellular iron and lipid peroxidation, EMT changes, and a shift toward glutamate utilization compared to control cell lines. Finally, CT IL-1α cells (but not the other constructs) were highly sensitive to the ferroptosis inducer RSL3. Together this work suggests that increased tumor IL-1α expression triggers a shift toward an oxidative and ferroptotic environment, leading to an aggressive tumor phenotype and drug resistance; but also reveals a unique vulnerability to agents that induce ferroptosis.