Disruption of endolysosomal trafficking pathways in glioma cells by methuosis-inducing indole-based chalcones
Nneka E Mbah1, Jean H Overmeyer1, William A Maltese2
1Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3000 Transverse Drive, Toledo, OH, 43614, USA.
Abstract:
Methuosis is a form of non-apoptotic cell death involving massive vacuolization of macropinosome-derived endocytic compartments, followed by a decline in metabolic activity and loss of membrane integrity. To explore the induction of methuosis as a potential therapeutic strategy for killing cancer cells, we have developed small molecules (indole-based chalcones) that trigger this form of cell death in glioblastoma and other cancer cell lines. Here, we report that in addition to causing fusion and expansion of macropinosome compartments, the lead compound, 3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (MOMIPP), disrupts vesicular trafficking at the lysosomal nexus, manifested by impaired degradation of EGF and LDL receptors, defective processing of procathepsins, and accumulation of autophagosomes. In contrast, secretion of the ectodomain derived from a prototypical type-I membrane glycoprotein, β-amyloid precursor protein, is increased rather than diminished. A closely related MOMIPP analog, which causes substantial vacuolization without reducing cell viability, also impedes cathepsin processing and autophagic flux, but has more modest effects on receptor degradation. A third analog, which causes neither vacuolization nor loss of viability, has no effect on endolysosomal trafficking. The results suggest that differential cytotoxicity of structurally similar indole-based chalcones is related, at least in part, to the severity of their effects on endolysosomal trafficking pathways.
Insights
Indole-based chalcones induce methuosis, a form of cell death marked by vacuolization, in cancer cells. The lead compound MOMIPP disrupts endolysosomal trafficking, offering a potential therapeutic strategy for glioblastoma.
Area of Science:
- Cell Biology
- Molecular Oncology
- Drug Discovery
Background:
- Methuosis is a non-apoptotic cell death pathway characterized by extensive vacuolization.
- Indole-based chalcones are being investigated for their potential to induce methuosis in cancer cells.
- Glioblastoma is an aggressive brain tumor with limited treatment options.
Purpose of the Study:
- To explore the induction of methuosis as a therapeutic strategy against cancer.
- To investigate the mechanism of action of indole-based chalcones that induce methuosis.
- To identify the key molecular targets responsible for the cytotoxic effects of these compounds.
Main Methods:
- Synthesis and characterization of indole-based chalcones.
- Treatment of glioblastoma and other cancer cell lines with synthesized compounds.
- Analysis of cellular morphology, including vacuolization and membrane integrity.
- Assessment of vesicular trafficking pathways, including endocytosis, lysosomal degradation, and autophagy.
- Evaluation of cell viability and metabolic activity.
Main Results:
- The lead compound, MOMIPP, induced methuosis in cancer cells, characterized by macropinosome fusion and expansion.
- MOMIPP disrupted lysosomal trafficking, impairing receptor degradation (EGF, LDL) and procathepsin processing, leading to autophagosome accumulation.
- A MOMIPP analog causing vacuolization but not cell death also affected cathepsin processing and autophagic flux, with milder effects on receptor degradation.
- A non-toxic analog showed no impact on endolysosomal trafficking, suggesting a correlation between trafficking disruption and cytotoxicity.
Conclusions:
- Indole-based chalcones, particularly MOMIPP, can effectively induce methuosis in cancer cells.
- The cytotoxicity of these compounds is linked to their ability to disrupt endolysosomal trafficking pathways.
- Targeting methuosis and vesicular trafficking represents a promising therapeutic avenue for glioblastoma and other cancers.
