ANGEL2 modulates wildtype TP53 translation and doxorubicin chemosensitivity in colon cancer.

Abstract

Multiple lines of correlative evidence support a role for ANGEL2, a novel cancer-relevant RNA-binding protein, in the modulation of chemoresistance and cancer patient survival. However, to date, no study has determined a mechanism by which ANGEL2 modulates cancer progression, nor its role in chemoresistance. Herein, we demonstrate that loss of ANGEL2 leads to a substantial decrease of the key tumor suppressor protein TP53. We show that ANGEL2 directly interacts with EIF4E, the rate limiting protein in cap-dependent translation. This interaction abrogates the ability for the TP53 translation repressor RBM38 to interact with EIF4E thereby enhancing TP53 translation. Loss of ANGEL2 in cancer cell lines resulted in increased 2D and 3D spheroid cell growth, and resistance to doxorubicin and etoposide. With therapeutic potential, treatment with Pep7, a seven amino-acid peptide derived from ANGEL2, rescued wildtype TP53 expression and sensitized cancer cells to doxorubicin. Together, we conclude that ANGEL2 modulates the EIF4E-RBM38 complex to enhance wildtype TP53 translation, and further, the Pep7 peptide may be explored as a therapeutic strategy for cancers which harbor wildtype TP53 expression. Implications: Loss of ANGEL2 contributes to decreased wildtype TP53 translation promoting doxorubicin resistance which can be rescued via an ANGEL2-derived peptide.