Abstract
Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors, but the mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Here we identify Snail as a strong transcriptional repressor of 4E-BP1. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Snail binds to three E-boxes present in the human 4E-BP1 promoter to repress transcription of 4E-BP1. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly represses 4E-BP1 expression, promotes cap-dependent translation in polysomes, and reduces the anti-proliferative effect of mTOR kinase inhibitors. Conversely, genetic and pharmacological inhibition of Snail function restores 4E-BP1 expression and sensitizes cancer cells to mTOR kinase inhibitors by enhancing 4E-BP1-mediated translation-repressive effect on cell proliferation and tumor growth. Our study reveals a critical Snail-4E-BP1 signaling axis in tumorigenesis, and provides a rationale for targeting Snail to improve mTOR-targeted therapies.
Highlights
Loss of 4E (eIF4E)-binding protein 1 (4E-BP1) expression has been linked to cancer progression and resistance to mammalian target of rapamycin (mTOR) inhibitors, but the mechanism underlying 4E-BP1 downregulation in tumors remains unclear
The multiple functions of mTOR are exerted by the formation of two distinct protein complexes, mTOR complex 1 and mTOR complex 2. mTORC1 regulates messenger RNA translation to promote protein synthesis and cell proliferation by phosphorylating two primary downstream effectors, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 70 kDa ribosomal protein S6 kinase 1. 4EBP1 is a translational repressor, which prevents the assembly of the eIF4F translation initiation complex by competing with eIF4G for binding to eIF4E, a 5′ mRNA cap-binding subunit of the eIF4F complex[2]
Using a dual luciferase reporter system that monitors the ratio between cap-dependent and -independent translation initiation[28,29], we found that expression of Snail in MCF7 and T47D cells significantly increased the cap-dependent translation rate but had no effect on initiation at internal ribosome entry sites (IRES)-driven cap-independent translation; in addition, Snail expression largely attenuated the cap-dependent translation inhibition induced by mTOR kinase inhibitors (mTORkis), AZD8055, and INK128 (Fig. 4a and Supplementary Fig. 7a)
Summary
Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors, but the mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Rapalogs have shown some success in specific tumor types and in patients with rare somatic TSC mutations[7], but their overall activity as a monotherapy is limited[6] This poor response might result from the weak inhibition of 4E-BP1 phosphorylation by rapalogs and induction of AKT activation through loss of the mTORC1/S6K-dependent negative feedback loops[1,6,8]. To overcome these issues, several new ATP-competitive mTOR kinase inhibitors (mTORkis) such as AZD80559 and INK12810, which inhibit both mTORC1 and mTORC2, have been developed and are being evaluated in clinical trials. We demonstrate that Snail acts as a reciprocal feedback suppressor of 4EBP1 expression by blocking the transcription of the 4E-BP1 gene, which mitigates the antitumor activities of mTORkis in cancer cells with overexpression of Snail
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
