The synergistic inhibition of breast cancer proliferation by combined treatment with 4EGI-1 and MK2206

Abstract

Cap-dependent translation is a potential cancer-related target (oncotarget) due to its critical role in cancer initiation and progression. 4EGI-1, an inhibitor of eIF4E/eIF4G interaction, was discovered by screening chemical libraries of small molecules. 4EGI-1 inhibits cap-dependent translation initiation by impairing the assembly of the eIF4E/eIF4G complex, and therefore is a potential anti-cancer agent. Here, we report that 4EGI-1 also inhibits mTORC1 signaling independent of its inhibitory role on cap-dependent translation initiation. The inhibition of mTORC1 signaling by 4EGI-1 activates Akt due to both abrogation of the negative feedback loops from mTORC1 to PI3K and activation of mTORC2. We further validated that mTORC2 activity is required for 4EGI-1-mediated Akt activation. The activated Akt counteracted the anticancer effects of 4EGI-1. In support of this model, inhibition of Akt potentiates the antitumor activity of 4EGI-1 both in vitro and in a xenograft mouse model in vivo. Our results suggest that a combination of 4EGI-1and Akt inhibitor is a rational approach for the treatment of cancer.

Keywords: 4EBP1; 4EBP1, eIF4E-binding protein 1; 4EGI-1; AKT; ER stress, endoplasmic reticulum stress; PI3K, phosphatidylinositol 3-kinase; cap-dependent translation; eIF4E; eIF4E, eukaryotic translation initiation factor 4E; eIF4F complex; mTORC1; mTORC1, mammalian target of rapamycin complex 1; mTORC2; mTORC2 mammalian target of rapamycin complex 2; p70S6K, ribosomal p70 S6 kinase.