Interaction of
RNA-binding protein RBM38 with
eIF4E on p53
mRNA is known to suppress p53 mRNA translation, which can be disrupted by an 8-amino
acid peptide (Pep8-YPYAASPA) derived from RBM38, leading to induction of p53 and
tumor suppression. Here, we rationally designed multiple Pep8 derivatives and screened for their binding affinities towards
eIF4E in silico. We showed that several key residues within Pep8 are necessary for its structure and function. We identified a shortened 7-amino
acid peptide (Pep7-PSAASPV) that has the highest affinity towards
eIF4E and is the most potent inducer of p53 expression. We found that iRGD is an effective vehicle to deliver Pep7 inside of cells for induction of p53 expression and growth suppression as compared to other
cell penetrating peptides (
Penetratin and Pep-1). We found that
peptide cyclization enhances Pep8 affinity for
eIF4E, induction of p53 and
tumor cell growth suppression. We also found that the ability of Pep7 to induce p53 expression and growth suppression is conserved in cells derived from canine
osteosarcoma, a spontaneous
tumor model frequently used for testing the feasibility of a therapeutic agent for human
cancer. Moreover, we showed that both human and canine
osteosarcoma cells, which are notoriously resistant to
radiation therapy, were sensitized by Pep7 to radiation-induced growth suppression and cell death. Together, our data suggest that Pep7 may be explored to sensitize
tumors to
radiation therapy.