| Summary: | Jing Ye, Xiaohua Jiang, Zhihuai Dong, Sunhong Hu, Mang Xiao Department of Otolaryngology Head and Neck Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Mang XiaoDepartment of Otolaryngology Head and Neck Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, East Qingchun Road Nr.3, Hangzhou, Zhejiang 310016, People’s Republic of ChinaEmail joelxm@zju.edu.cnIntroduction: 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
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