RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels
Open accessAbstract
Therapeutics that discriminate between the genetic makeup of normal cells and tumour cells are valuable for treating and understanding cancer. Small molecules with oncogene-selective lethality may reveal novel functions of oncoproteins and enable the creation of more selective drugs. Here we describe the mechanism of action of the selective anti-tumour agent erastin, involving the RAS-RAF-MEK signalling pathway functioning in cell proliferation, differentiation and survival. Erastin exhibits greater lethality in human tumour cells harbouring mutations in the oncogenes HRAS, KRAS or BRAF. Using affinity purification and mass spectrometry, we discovered that erastin acts through mitochondrial voltage-dependent anion channels (VDACs)--a novel target for anti-cancer drugs. We show that erastin treatment of cells harbouring oncogenic RAS causes the appearance of oxidative species and subsequent death through an oxidative, non-apoptotic mechanism. RNA-interference-mediated knockdown of VDAC2 or VDAC3 caused resistance to erastin, implicating these two VDAC isoforms in the mechanism of action of erastin. Moreover, using purified mitochondria expressing a single VDAC isoform, we found that erastin alters the permeability of the outer mitochondrial membrane. Finally, using a radiolabelled analogue and a filter-binding assay, we show that erastin binds directly to VDAC2. These results demonstrate that ligands to VDAC proteins can induce non-apoptotic cell death selectively in some tumour cells harbouring activating mutations in the RAS-RAF-MEK pathway.
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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 [13]
Lipophilic antioxidants suppress erastin-induced death, implicating lipophilic reactive oxygen species in this process.
“Further studies [13, 17] identified lipophilic antioxidants (α-tocopherol, butylated hydroxytoluene and β-carotene) as strong suppressors of erastin-induced cell death, suggesting that reactive oxygen species (ROS), likely lipophilic in nature, were involved in this cell death process.”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [13]
Erastin causes ROS production in sensitive cell lines, as detected with DCF.
“Indeed, analysis with dichlorofluorescein (DCF), a ROS-detecting dye, revealed that erastin causes the generation of ROS in sensitive cell lines [10, 13].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [13]
Ferroptosis is a unique cell death pathway distinct from apoptosis, reliant on availability of iron liberated through ferritinophagy.
“Ferroptosis, a unique cell death pathway distinct from apoptosis [62], [66], [80], is reliant on the availability of iron [62], [66], [81] liberated through ferritinophagy [63].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [80]
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- Authors
- Yagoda, N., von Rechenberg, M., Zaganjor, E., Bauer, A. J., Yang, W. S., Fridman, D. J., Wolpaw, A. J., Smukste, I., Peltier, J. M., Boniface, J. J., Smith, R., Lessnick, S. L., Sahasrabudhe, S., & Stockwell, B. R.
- Affiliations
- Huntsman Cancer Institute (US)
- Columbia University (US)
- Corresponding author
- Stockwell, Brent R.
- ORCID
- Venue
- Nature
- Published
- 2007-06
- Volume
- 447
- Issue
- 7146
- Pages
- 865-869
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3047570
- OpenAlex
- W1975617209
- Cited by
- 1,631
- References
- 3
- Citations by year
- 2026: 89 · 2025: 183 · 2024: 238 · 2023: 216 · 2022: 228 · 2021: 181 · 2020: 97 · 2019: 73 · 2018: 54 · 2017: 67 · 2016: 42 · 2015: 30 · 2014: 29 · 2013: 16 · 2012: 16
- FWCI
- 7.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (R01CA097061)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- erastin, RAS/RAF/MEK pathway, mitochondrial voltage-dependent anion channel, VDAC2, VDAC3, oxidative cell death, non-apoptotic cell death, HRAS mutation, KRAS mutation, BRAF mutation, mitochondrial outer membrane permeabilization, tumor cell killing
- MeSH terms
- Humans, Phosphorylation, Piperazines, Sensitivity and Specificity, Signal Transduction, Ion Channel Gating, Cell Death, Oxidative Stress, ras Proteins, Mitogen-Activated Protein Kinase Kinases, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, raf Kinases, Voltage-Dependent Anion Channel 2
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