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ANGEL2 Modulates Wild-type TP53 Translation and Doxorubicin Chemosensitivity in Colon Cancer
Christopher August Lucchesi1,2, Saisamkalpa Mantrala1, Darren Tran1
1VA Northern California Health Care System, Mather, California.
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.
Insights
The RNA-binding protein ANGEL2 enhances TP53 translation by interacting with EIF4E, preventing repressor RBM38 binding. Loss of ANGEL2 increases chemoresistance, but a peptide derived from ANGEL2 restores TP53 levels and drug sensitivity.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- The RNA-binding protein ANGEL2 is implicated in cancer chemoresistance and patient survival.
- The precise mechanisms by which ANGEL2 influences cancer progression and chemoresistance remain largely undetermined.
Purpose of the Study:
- To elucidate the mechanism by which ANGEL2 modulates cancer progression and chemoresistance.
- To investigate the role of ANGEL2 in regulating the translation of the tumor suppressor protein TP53.
Main Methods:
- Investigated the interaction between ANGEL2 and EIF4E (eukaryotic translation initiation factor 4E).
- Assessed the impact of ANGEL2 on the interaction between EIF4E and the TP53 translation repressor RBM38.
- Utilized cancer cell lines to evaluate the effects of ANGEL2 loss on cell growth and chemoresistance.
- Administered an ANGEL2-derived peptide (Pep7) to assess its therapeutic potential.
Main Results:
- Loss of ANGEL2 significantly decreased the expression of the tumor suppressor protein TP53.
- ANGEL2 directly binds to EIF4E, inhibiting the interaction of RBM38 with EIF4E and thereby enhancing TP53 translation.
- Depletion of ANGEL2 in cancer cells led to increased spheroid growth and resistance to doxorubicin and etoposide.
- Treatment with the Pep7 peptide restored wildtype TP53 expression and sensitized cancer cells to doxorubicin.
Conclusions:
- ANGEL2 plays a crucial role in cancer by modulating the EIF4E-RBM38 complex to promote wildtype TP53 translation.
- Loss of ANGEL2 contributes to chemoresistance through decreased TP53 translation.
- The ANGEL2-derived peptide Pep7 shows therapeutic potential for treating cancers with wildtype TP53 expression.
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