Low-Concentration PTX And RSL3 Inhibits Tumor Cell Growth Synergistically By Inducing Ferroptosis In Mutant p53 Hypopharyngeal Squamous Carcinoma

INTRODUCTION: RSL3-induced ferroptosis is a cell death pathway dependent upon intracellular iron and is characterized by accumulation of lipid hydroperoxides. Glutaminolysis, a glutamine-fueled intracellular metabolic pathway, is an essential pathway of ferroptosis in cancer cells. Recent findings showed low-concentration paclitaxel (PTX) could inhibit cell death by upregulating p53 expression; downregulating glutaminolysis-related genes. METHODS: The therapeutic effect of RSL3 plus low-concentration PTX combination therapy was investigated in HPSCC cells harboring mutant p53 (mtp53). Relative cell viability, ferroptosis-specific lipid peroxidation and relevant protein expression were evaluated. RESULTS: We demonstrated that neither PTX nor RSL3 in low concentration caused significant cell death; however, the combination therapy is shown to induce ferroptosis and significant cell death in mtp53 HPSCC. We discovered that low-concentration PTX enhanced the RSL3-induced ferroptosis by upregulating mtp53 expression. Furthermore, mtp53-mediated transcriptional regulation of SLC7A11 could be the key determinant. DISCUSSION: Although gain-of-function of p53 variants remains to be characterized, our findings provide new insight into the synergistical cell death by regulating ferroptosis and p53.