Modulatory profiling identifies mechanisms of small molecule-induced cell death
Open accessAbstract
Cell death is a complex process that plays a vital role in development, homeostasis, and disease. Our understanding of and ability to control cell death is impeded by an incomplete characterization of the full range of cell death processes that occur in mammalian systems, especially in response to exogenous perturbations. We present here a general approach to address this problem, which we call modulatory profiling. Modulatory profiles are composed of the changes in potency and efficacy of lethal compounds produced by a second cell death-modulating agent in human cell lines. We show that compounds with the same characterized mechanism of action have similar modulatory profiles. Furthermore, clustering of modulatory profiles revealed relationships not evident when clustering lethal compounds based on gene expression profiles alone. Finally, modulatory profiling of compounds correctly predicted three previously uncharacterized compounds to be microtubule-destabilizing agents, classified numerous compounds that act nonspecifically, and identified compounds that cause cell death through a mechanism that is morphologically and biochemically distinct from previously established ones.
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Erastin- and RSL3-induced death is non-apoptotic, occurring without apoptotic hallmarks and even when core apoptosis machinery is suppressed.
“The mode of cell death induced by these compounds was surprisingly found to be non-apoptotic, as cells treated with erastin and RSL3 died in the absence of apoptotic hallmarks [11, 12, 13], and in cells where the core apoptosis machinery – caspases, BAX, and BAK was suppressed [14].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [14]
In modulatory profiling, erastin and RSL3 cluster together, suggesting they share a cell death mechanism.
“Using modulatory profiling, an unbiased pharmacological and genetic profiling system in which lethal compounds are classified based on their functional profiles [14, 18], erastin and RSL3 were found to cluster together, suggesting that they share a similar cell death mechanism.”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [14]
Ferroptosis is an iron-dependent autophagic cell death program that can be inhibited in MEFs by genetically inactivating autophagy or ferritinophagy.
“an iron-dependent autophagic cell death program [62], [63], [64] that can be inhibited in MEFs by genetically inactivating autophagy or ferritinophagy [65].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [64]
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Wolpaw, A. J., & Stockwell, B. R. (2014) · Methods in Enzymology · doi:10.1016/b978-0-12-801430-1.00011-1 · Cited by 10 · see citing works
Self-citation
- Authors
- Wolpaw, A. J., Shimada, K., Skouta, R., Welsch, M. E., Akavia, U. D., Pe'er, D., Shaik, F., Bulinski, J. C., & Stockwell, B. R.
- Affiliations
- Department of Biological Sciences,
- Department of Biological Sciences (RU)
- Department of Chemistry,
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-09-06
- Volume
- 108
- Issue
- 39
- Pages
- E771-80
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3182736
- OpenAlex
- W2171713242
- Cited by
- 133
- References
- 69
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 15 · 2022: 7 · 2021: 10 · 2020: 14 · 2019: 9 · 2018: 6 · 2017: 11 · 2016: 8 · 2015: 9 · 2014: 9 · 2013: 5 · 2012: 11
- FWCI
- 3.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Columbia Academic Commons (Columbia University)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (RC2CA148308, R01CA097061, R01CA136779)
- National Institute of General Medical Sciences (R01GM085081)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- cell death, cell death mechanisms, microtubule destabilizing agents, compound classification, gene expression profiles, human cell lines
- MeSH terms
- Cell Line, Humans, Microtubules, Signal Transduction, Cell Death, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
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