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 .
Keywords: HPSCC, ferroptosis, low-concentration paclitaxel, RSL3, synthetic cell death, mtp53, SLC7A11, GOF p53 variants