Abstract
The eIF3e protein is a component of the multisubunit eIF3 complex, which is essential for cap-dependent translation initiation. Decreased eIF3e expression is often observed in breast and lung cancer and has been shown to induce epithelial-to-mesenchymal transition (EMT) in breast epithelial cells by an unknown mechanism. Here, we study the effect of decreased eIF3e expression in lung epithelial cells by creating stable clones of lung epithelial cells (A549) that express an eIF3e-targeting shRNA. Our data indicate that decreased eIF3e expression in lung epithelial cells leads to EMT, as it does in breast epithelial cells. Importantly, we show that decreased eIF3e expression in both lung and breast epithelial cells leads to the overproduction of the TGFβ cytokine and that inhibition of TGFβ signaling can reverse eIF3e-regulated EMT in lung epithelial cells. In addition, we discovered that several mRNAs that encode important EMT regulators are translated by a cap-independent mechanism when eIF3e levels are reduced. These findings indicate that EMT mediated by a decrease in eIF3e expression may be a general phenomenon in epithelial cells and that it requires activation and maintenance of the TGFβ signaling pathway. These results indicate that inhibition of TGFβ signaling could be an efficient way to prevent metastasis in patients with NSCLC that display reduced eIF3e expression.
Highlights
EIF3e is a core component of the eIF3 multisubunit translation initiation complex, which binds directly to both the 40S ribosomal subunit and the cap-binding complex to facilitate ribosome recruitment to mRNA [1]
A recent study found that expression of a truncated eIF3e protein that lacks normal eIF3e activity causes both a decrease in global, cap-dependent translation initiation, and a concomitant increase in an alternative initiation mechanism that relies on RNA structures called internal ribosome entry sites (IRES; ref. 3), suggesting that decreased eIF3e activity creates an
Some translation initiation factors have been shown to be involved in cancer development and progression [4], most notably the cap-binding protein eIF4E [5] whose overexpression has been correlated with many types of cancer [6], including breast [7, 8] and lung [9] cancers. eIF3e is involved in cancer development, as loss of heterozygosity for the human eIF3e gene (INT6) is found in 21% to 28% of breast tumors and reduced eIF3e expression is found in 37% of breast cancers [10, 11]
Summary
EIF3e is a core component of the eIF3 multisubunit translation initiation complex, which binds directly to both the 40S ribosomal subunit and the cap-binding complex to facilitate ribosome recruitment to mRNA [1]. Some translation initiation factors have been shown to be involved in cancer development and progression [4], most notably the cap-binding protein eIF4E [5] whose overexpression has been correlated with many types of cancer [6], including breast [7, 8] and lung [9] cancers. Our data indicate that the induction of TGFb production and signaling is essential for eIF3e-regulated EMT in A549 lung cancer cells
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