Targeting Translational Control in Cancer Using Small Molecule Activators of PP2A
Abstract
Cancer cells rely on hyperactive protein synthesis to reprogram the proteome to sustain the transformed phenotype. Thus, aberrant protein translation has emerged as a promising therapeutic target. Cap‐dependent translation is an exquisitely regulated process that requires the assembly of the eIF4F translation initiation complex. The rate limiting component of the eIF4F complex is eIF4E, which binds to the 5’ cap structure of mRNAs to initiate translation. Cap‐dependent translation is kept in check by the translation repressor 4E‐BP1; in its active hypophosphorylated form, 4E‐BP1 sequesters eIF4E to prevent translation initiation. Cancer cells use several mechanisms to bypass 4E‐BP1 translational suppression, including hyperactivation of mTORC1 for hyperphosphorylation and inactivation of 4E‐BP1; inactivation of the 4E‐BP1 phosphatase, PP2A; and profound suppression of 4E‐BP1 expression. We have found that the expression and activity of 4E‐BP1 can be restored in tumor cells using novel small molecule activators of PP2A (SMAPs), a class of compounds that activate selected PP2A tumor suppressors and are being actively developed as anticancer agents (Leonard et al. Cell, 2020). The objective of this study was to investigate the mechanism(s) by which SMAPs lead to restoration of the expression and activity of 4E‐BP1 in cancer cells for inhibition of hyperactive protein translation and tumor suppression.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 01, 2022
- Source ID
- 10.1096/fasebj.2022.36.s1.l7668
Entities
People
- Adrian R. Black
- Black D. Jennifer
- Goutham Narla
- Kayla A. Jonas
- Michelle A. Lum
Organizations
- United States Department of Defense
- University of Michigan
- University of Nebraska–Lincoln