Time Course of Changes in Sorafenib‐Treated Hepatocellular Carcinoma Cells Suggests Involvement of Phospho‐Regulated Signaling in Ferroptosis Induction

Abstract

Ferroptosis is a form of regulated, non-apoptotic cell death characterized by excessive lipid peroxidation that can be triggered by inhibition of the cystine-glutamate antiporter, system X c − . Sorafenib, an FDA-approved multi-kinase inhibitor drug that is used for treatment of hepatocellular carcinoma (HCC), has been shown to induce ferroptosis. Protein phosphorylation changes upon sorafenib treatment have been previously reported in patient studies and in cell culture. However, early phosphorylation changes during induction of ferroptosis are not reported. This work highlights these changes through a time course from 7 to 60 min of sorafenib treatment in human (SKHep1) HCC cells. A total of 6170 unique phosphosites from 2381 phosphoproteins are quantified, and phosphorylation changes occur after as little as 30 min of sorafenib treatment. By 60 min, notable changes included phosphosites significantly changing on p53 (P04637), CAD protein (P27708), and proteins important for iron homeostasis, such as heavy chain ferritin (FTH1; P02794), heme oxygenase 1 (HMOX1; P09601), and PCBP1 (Q15365). Additional sites on proteins in key regulatory pathways are identified, including sites in ferroptosis-related proteins, indicating the likely involvement of phospho-regulated signaling during ferroptosis induction.

Oxidative Medicine and Cellular Longevity Hsa_circ_0013731 mediated by E2F1 inhibits ferroptosis in hepatocellular carcinoma cells by sponging miR-877-3p and targeting SLC7A11

“…Increasing evidences have showed that ferroptosis acts important roles in HCC treatment. Ferroptosis is a vital part of mechanisms for sorafenib, which is rst line therapy for HCC [29]. LDL-DHA nanoparticles, a potential new drug for HCC, cause ferroptosis in HCC tissues [30].…”

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

“…Recently, another publication contributed to a better understanding of the mode of ferroptosis induction in HCC cells by sorafenib. The authors found that sorafenib treatment for 60 min resulted in changes at phosphorylation sites of proteins that are involved in iron homeostasis and of proteins that are part of ferroptosis-related pathways [ 83 ]. However, there are also reports that sorafenib fails to trigger ferroptosis in different cancer cell lines including HCC [ 93 ], which might indicate cell line-specific effects, other (molecular) factors that contribute to the sensitivity of sorafenib-induced ferroptosis or both.…”

Global Characteristics and Trends in Research on Ferroptosis: A Data-Driven Bibliometric Study

“…Although the underlying mechanisms of HCC are not fully understood, the discovery of ferroptosis brings new light to its diagnosis and treatment. Sorafenib, a first-line drug with multikinase inhibitory properties that is used as a reference treatment in advanced HCC, has been investigated intensively to induce ferroptosis in HCC cells [43,44]. Mechanistically, the ferroptosis-inducing effect of sorafenib is due to upregulation of phosphorylation of ferroptosis-related genes or proteins, such as CAD protein (P27708), heavy chain ferritin (FTH1; P02794), and heme oxygenase 1 (HMOX1; 9 Oxidative Medicine and Cellular Longevity P09601) [43].…”

“…Sorafenib, a first-line drug with multikinase inhibitory properties that is used as a reference treatment in advanced HCC, has been investigated intensively to induce ferroptosis in HCC cells [43,44]. Mechanistically, the ferroptosis-inducing effect of sorafenib is due to upregulation of phosphorylation of ferroptosis-related genes or proteins, such as CAD protein (P27708), heavy chain ferritin (FTH1; P02794), and heme oxygenase 1 (HMOX1; 9 Oxidative Medicine and Cellular Longevity P09601) [43]. However, sorafenib does not seem to be a bonafide ferroptosis inducer when applied to other cancers [45].…”