Work

ANGEL2 Modulates Wild-type TP53 Translation and Doxorubicin Chemosensitivity in Colon Cancer

Year: 2025

Type: article

Abstract: Multiple lines of correlative evidence support a role for angel homolog 2 (ANGEL2), a novel cancer-relevant RNA-binding protein, in the modulation of chemoresistance and survival of patients with cancer. However, to date, no study has determined a mechanism by which ANGEL2 modulates cancer progression, nor its role in chemoresistance. In this study, we demonstrate that loss of ANGEL2 leads to a substantial decrease in the key tumor-suppressor protein tumor protein p53 (TP53). We show that ANGEL2 directly interacts with eukaryotic translation initiation factor 4E (EIF4E), the rate-limiting protein in cap-dependent translation. This interaction abrogates the ability of the TP53 translation repressor RNA-binding motif protein 38 to interact with EIF4E, thereby enhancing TP53 translation. Loss of ANGEL2 in cancer cell lines resulted in increased two-dimensional and three-dimensional spheroid cell growth and resistance to doxorubicin and etoposide. With therapeutic potential, treatment with Pep7, a seven-amino-acid peptide derived from ANGEL2, rescued wild-type (WT) TP53 expression and sensitized cancer cells to doxorubicin. Together, we conclude that ANGEL2 modulates the EIF4E-RNA-binding motif protein 38 complex to enhance WT TP53 translation, and furthermore, the Pep7 peptide may be explored as a therapeutic strategy for cancers that harbor WT TP53 expression. IMPLICATIONS: Loss of ANGEL2 contributes to decreased WT TP53 translation promoting doxorubicin resistance, which can be rescued via an ANGEL2-derived peptide.

Source: Molecular Cancer Research

DOI: 10.1158/1541-7786.mcr-24-0702