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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.

SUBMITTER: Wang H

PROVIDER: S-EPMC4614875 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Wang Hongtao H Huang Fang F Wang Jian J Wang Peng P Lv Wenjie W Hong Liu L Li Shanhu S Zhou Jianguang J

Cell cycle (Georgetown, Tex.) 20150101 2

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 r ...[more]

PMID: 25607647

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

Publications

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

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