Distinct TP53 Mutation Types Exhibit Increased Sensitivity to Ferroptosis Independently of Changes in Iron Regulatory Protein Activity

Abstract

The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer. In addition to loss of tumor suppressor functions, mutations in TP53 promote cancer progression by altering cellular iron acquisition and metabolism. A newly identified role for TP53 in the coordination of iron homeostasis and cancer cell survival lies in the ability for TP53 to protect against ferroptosis, a form of iron-mediated cell death. The purpose of this study was to determine the extent to which TP53 mutation status affects the cellular response to ferroptosis induction. Using H1299 cells, which are null for TP53, we generated cell lines expressing either a tetracycline inducible wild-type (WT) TP53 gene, or a representative mutated TP53 gene from six exemplary “hotspot” mutations in the DNA binding domain (R273H, R248Q, R282W, R175H, G245S, and R249S). TP53 mutants (R273H, R248Q, R175H, G245S, and R249S) exhibited increased sensitivity ferroptosis compared to cells expressing WT TP53. As iron-mediated lipid peroxidation is critical for ferroptosis induction, we hypothesized that iron acquisition pathways would be upregulated in mutant TP53-expressing cells. However, only cells expressing the R248Q, R175H, and G245S TP53 mutation types exhibited statistically significant increases in spontaneous iron regulatory protein (IRP) RNA binding activity following ferroptosis activation. Moreover, changes in the expression of downstream IRP targets were inconsistent with the observed differences in sensitivity to ferroptosis. These findings reveal that canonical iron regulatory pathways are bypassed during ferroptotic cell death. These results also indicate that induction of ferroptosis may be an effective therapeutic approach for tumor cells expressing distinct TP53 mutation types.

Multi-omics Analysis of Ferroptosis Regulation Patterns and Characterization of Tumor Microenvironment in Patients with Oral Squamous Cell Carcinoma

“…Furthermore, we found that the low FPscore subtype showed more TP53 mutations than the high FPscore subtype; additionally, the TP53 pathway was activated in tumors with a high FPscore (Figure 4C; Figure 5G). Therefore, these findings indicate that TP53 may regulate ferroptosis in OSCC cells and are consistent with those of recent studies showing that TP53 and the tumor-associated mutant TP53 may play import roles in ferroptosis of cancer cells [53,54].…”

Auranofin reveals therapeutic anticancer potential by triggering distinct molecular cell death mechanisms and innate immunity in mutant p53 non-small cell lung cancer

“…Contrary to our results, lipid peroxidation in the mutant p53 R273H NCI–H1299 cells did not increase in response to erastin, due to their higher levels of basal lipid peroxidation. Altogether, the mechanisms contributing to increased ferroptotic sensitivity in mutant p53 expressing cells are complex and may not be consistent between distinct TP53 mutation types [ 71 , 75 ]. However, with AF, we were able to kill p53 R273H overexpressing cells in a ferroptotic fashion via GPX4 inactivation and lipid peroxidation.…”

The Effect of Ferroptosis-Related Genes on Prognosis and Tumor Mutational Burden in Hepatocellular Carcinoma

“…TP53 is a well-known tumor suppressor gene involved in regulating the cell cycle and negative regulation of cell division by a series of genes [ 23 , 24 ]. Recent studies have found that TP53 can have a role in the process of ferroptosis [ 25 , 26 ]. Numerous studies have taken TP53 as a marker gene of ferroptosis.…”