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Cellular toxicity of iHAP1 and DT-061 does not occur through PP2A-B56 targeting
Open accessPreprint — published as 10.15252/embj.2022110611 · Paper page
Abstract
PP2A is an abundant phosphoprotein phosphatase that acts as a tumor suppressor. For this reason, compounds able to activate PP2A are attractive anticancer agents. The small molecule compounds iHAP1 and DT-061 have recently been reported by Leonard et al. (2020) and Morita et al. (2020) in Cell to selectively stabilize specific PP2A-B56 complexes which mediate cell killing. Here, we show that this is not the case and question key findings in these papers. Through genome wide CRISPR-Cas9 screens, we uncover the biological pathways targeted by these compounds. We find that iHAP1 directly blocks microtubule assembly both in vitro and in vivo and thus acts as a microtubule poison. In contrast, DT-061 disrupts both the Golgi apparatus and the endoplasmic reticulum and we directly visualize DT-061 in cytoplasmic granules that co-localize with Golgi markers. Our work demonstrates that iHAP1 and DT-061 cannot be used for dissecting PP2A-B56 biology.
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Metadata
- Authors
- Vit, G., Duro, J., Rajendraprasad, G., Hertz, E. P. T., Kauffeldt Holland, L. K., Weisser, M. B., McEwan, B. C., Lopez-Mendez, B., Montoya, G., Mailand, N., Maeda, K., Kettenbach, A., Barisic, M., & Nilsson, J.
- Affiliations
- University of Copenhagen (DK)
- Danish Cancer Society (DK)
- Dartmouth College (US)
- Corresponding author
- Nilsson, Jakob
- ORCID
- Venue
- The EMBO Journal
- Publisher
- openRxiv
- Published
- 2021-07-09
- Volume
- 41
- Issue
- 14
- Pages
- e110611-e110611
- ISSN
- 0261-4189 (ISSN-L)
- PMC
- PMC9289710
- OpenAlex
- W4282828326
- Cited by
- 33
- References
- 1
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 9 · 2023: 5 · 2022: 5 · 2021: 1
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- The EMBO Journal (publishedVersion, other-oa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, cc-by)
- Funders
- Kræftens Bekæmpelse (R146‐A9322, R269-A15586-B17)
- Wellcome Trust (202811/Z/16/Z, 202811)
- Danish Cancer Society Research Center (R146‐A9322, R269‐A15586‐B17)
- Lundbeckfonden (NNF14CC0001, 2017-3212, R215‐2015-4081)
- Novo Nordisk (NNF14CC0001, NNF17CC0027852)
- Danish e-Infrastructure Cooperation
- Novo Nordisk Fonden (NNF 14CC0001, NNF18OC0030752, NNF18OC0032996, (grant NNF14CC0001), NNF17CC0027852, NNF20OC0065098, NNF19OC0058504, NNF18CC0033876, NNF18OC0053124)
- Danmarks Frie Forskningsfond (6108–00542B, 7016‐00055, 0134‐00199B, 8021‐00101B)
- H. Lundbeck A/S
- National Institutes of Health
- National Cancer Institute (R33CA225458)
- National Institute of General Medical Sciences (R35GM119455)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- protein phosphatase 2A, PP2A activators, synthetic lethality, microtubule assembly inhibition, Golgi apparatus, endoplasmic reticulum, lipogenesis, anticancer agents
- MeSH terms
- Protein Processing, Post-Translational, Apoptosis, Protein Phosphatase 2
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