Active Ras Triggers Death in Glioblastoma Cells through Hyperstimulation of Macropinocytosis
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Abstract
Expression of activated Ras in glioblastoma cells induces accumulation of large phase-lucent cytoplasmic vacuoles, followed by cell death. This was previously described as autophagic cell death. However, unlike autophagosomes, the Ras-induced vacuoles are not bounded by a double membrane and do not sequester organelles or cytoplasm. Moreover, they are not acidic and do not contain the autophagosomal membrane protein LC3-II. Here we show that the vacuoles are enlarged macropinosomes. They rapidly incorporate extracellular fluid-phase tracers but do not sequester transferrin or the endosomal protein EEA1. Ultimately, the cells expressing activated Ras detach from the substratum and rupture, coincident with the displacement of cytoplasm with huge macropinosome-derived vacuoles. These changes are accompanied by caspase activation, but the broad-spectrum caspase inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethylketone does not prevent cell death. Moreover, the majority of degenerating cells do not exhibit chromatin condensation typical of apoptosis. These observations provide evidence for a necrosis-like form of cell death initiated by dysregulation of macropinocytosis, which we have dubbed “methuosis.” An activated form of the Rac1 GTPase induces a similar form of cell death, suggesting that Ras acts through Rac-dependent signaling pathways to hyperstimulate macropinocytosis in glioblastoma. Further study of these signaling pathways may lead to the identification of other chemical and physiologic triggers for this unusual form of cell death. (Mol Cancer Res 2008;6(6):965–77)
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Macropinocytosis has been reported in cell death of glioblastoma cancer cells with constitutive H-Ras activation in glioblastoma cell line U251, resulting in accumulation of macropinosomes and vacuolization of the cells.
“Moreover, macropinocytosis has been also reported in cell death of glioblastoma cancer cells with constitutive H-Ras activation in glioblastoma cell line U251, resulting in the accumulation macropinosomes and vacuolization of the cells [124].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [124]
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- Authors
- Overmeyer, J. H., Kaul, A., Johnson, E. E., & Maltese, W. A.
- Affiliations
- University of Toledo (US)
- Venue
- Molecular Cancer Research
- Published
- 2008-06-01
- Volume
- 6
- Issue
- 6
- Pages
- 965-977
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC2994605
- OpenAlex
- W2018951108
- Cited by
- 229
- References
- 56
- Citations by year
- 2026: 10 · 2025: 30 · 2024: 22 · 2023: 15 · 2022: 14 · 2021: 16 · 2020: 12 · 2019: 9 · 2018: 14 · 2017: 12 · 2016: 16 · 2015: 12 · 2014: 14 · 2013: 10 · 2012: 7
- FWCI
- 2.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01 CA 34569, R01CA034569, R01CA115495)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- activated Ras, glioblastoma, macropinocytosis, methuosis, necrosis-like cell death, macropinosomes, Rac1 GTPase, caspase activation, cytoplasmic vacuoles, cell detachment
- MeSH terms
- Brain Neoplasms, Glioblastoma, Humans, Necrosis, Pinocytosis, Vacuoles, Proto-Oncogene Proteins p21(ras), rac1 GTP-Binding Protein, Cell Line, Tumor
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