Disruption of endolysosomal trafficking pathways in glioma cells by methuosis-inducing indole-based chalcones.
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.
Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3000 Transverse Drive, Toledo, OH, 43614, USA.
Nneka E
NE
Mbah
Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3000 Transverse Drive, Toledo, OH, 43614, USA.
Jean H
JH
Overmeyer
Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3000 Transverse Drive, Toledo, OH, 43614, USA. william.maltese@utoledo.edu.
William A
WA
Maltese
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D011992:Endosomes / Q000187:drug effects* / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
C573286:3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one; D016564:Amyloid beta-Protein Precursor; D047188:Chalcones; D006023:Glycoproteins; D007211:Indoles; D011725:Pyridines; C030374:indole
Cell death; Chalcones; Endosomes; Lysosomes; Macropinocytosis; Methuosis