Advertisement

ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI176093

Small molecule modulators of B56-PP2A restore 4E-BP function to suppress eIF4E-dependent translation in cancer cells

Michelle A. Lum,1 Kayla A. Jonas,2 Shreya Parmar,2 Adrian R. Black,1 Caitlin M. O'Connor,3 Stephanie Dobersch,4 Naomi Yamamoto,4 Tess M. Robertson,4 Aidan Schutter,4 Miranda Giambi,3 Rita A. Avelar,5 Analisa DiFeo,5 Nicholas T. Woods,1 Sita Kugel,4 Goutham Narla,3 and Jennifer D. Black1

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Lum, M. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Jonas, K. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Parmar, S. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Black, A. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by O'Connor, C. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Dobersch, S. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Yamamoto, N. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Robertson, T. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Schutter, A. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Giambi, M. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Avelar, R. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by DiFeo, A. in: JCI | PubMed | Google Scholar |

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Woods, N. in: JCI | PubMed | Google Scholar |

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Kugel, S. in: JCI | PubMed | Google Scholar

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Narla, G. in: JCI | PubMed | Google Scholar |

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

2Eppley Insitute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States of America

3Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

4Human Biology Division, Fred Hutchinson Cancer Center, Seattle, United States of America

5Department of Pathology, University of Michigan, Ann Arbor, United States of America

Find articles by Black, J. in: JCI | PubMed | Google Scholar

Published January 27, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI176093.
Copyright © 2025, Lum et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 27, 2025 - Version history
View PDF
Abstract

Dysregulated eIF4E-dependent translation is a central driver of tumorigenesis and therapy resistance. eIF4E binding proteins (4E-BP1/2/3) are major negative regulators of eIF4E-dependent translation that are inactivated in tumors through inhibitory phosphorylation or downregulation. Previous studies have linked PP2A phosphatase(s) to activation of 4E-BP1. Here, we leveraged biased small molecule activators of PP2A (SMAPs) to explore the role of B56-PP2A(s) in 4E-BP regulation and the potential of B56-PP2A activation for restoring translational control in tumors. SMAP treatment promoted PP2A-dependent hypophosphorylation of 4E-BP1/2, supporting a role for B56-PP2As (e.g., B56α-PP2A) as 4E-BP phosphatases. Unexpectedly, SMAPs induced transcriptional upregulation of 4E-BP1 through a B56 PP2A→TFE3/TFEB→ATF4 axis. Cap-binding and co-immunoprecipitation assays showed that B56-PP2A(s) activation blocks assembly of the eIF4F translation initiation complex, and cap-dependent translation assays confirmed the translation inhibitory effects of SMAPs. Thus, B56-PP2A(s) orchestrate a translation repressive program involving transcriptional induction and activation of 4E-BP1. Notably, SMAPs promoted 4E-BP1-dependent apoptosis in tumor cells and potentiated 4E-BP1 function in the presence of ERK or mTOR inhibitors, agents that rely on inhibition of eIF4E-dependent translation for antitumor activity. These findings, combined with the ability of SMAPs to regulate 4E-BP1 in vivo, highlight the potential of PP2A activators for cancer therapy and overcoming therapy resistance.

Supplemental material

View Unedited blot and gel images

View

Version history
  • Version 1 (January 27, 2025): In-Press Preview
Advertisement
Advertisement