title: Ophiobolin A induces paraptosis-like cell death in human glioblastoma cells by decreasing BKCa channel activity.
abstract: Glioblastoma multiforme (GBM) is the most lethal and common malignant human brain tumor. The intrinsic resistance of highly invasive GBM cells to radiation- and chemotherapy-induced apoptosis accounts for the generally dismal treatment outcomes. This study investigated ophiobolin A (OP-A), a fungal metabolite from Bipolaris species, for its promising anticancer activity against human GBM cells exhibiting varying degrees of resistance to proapoptotic stimuli. We found that OP-A induced marked changes in the dynamic organization of the F-actin cytoskeleton, and inhibited the proliferation and migration of GBM cells, likely by inhibiting big conductance Ca(2+)-activated K(+) channel (BKCa) channel activity. Moreover, our results indicated that OP-A induced paraptosis-like cell death in GBM cells, which correlated with the vacuolization, possibly brought about by the swelling and fusion of mitochondria and/or the endoplasmic reticulum (ER). In addition, the OP-A-induced cell death did not involve the activation of caspases. We also showed that the expression of BKCa channels colocalized with these two organelles (mitochondria and ER) was affected in this programmed cell death pathway. Thus, this study reveals a novel mechanism of action associated with the anticancer effects of OP-A, which involves the induction of paraptosis through the disruption of internal potassium ion homeostasis. Our findings offer a promising therapeutic strategy to overcome the intrinsic resistance of GBM cells to proapoptotic stimuli.
authors.affiliation: Laboratoire de Toxicologie, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Bury
authors.forename: A
authors.initials: A
authors.lastname: Girault
authors.forename: V
authors.initials: V
authors.lastname: Mégalizzi
authors.forename: S
authors.initials: S
authors.lastname: Spiegl-Kreinecker
authors.forename: V
authors.initials: V
authors.lastname: Mathieu
authors.forename: W
authors.initials: W
authors.lastname: Berger
authors.forename: A
authors.initials: A
authors.lastname: Evidente
authors.forename: A
authors.initials: A
authors.lastname: Kornienko
authors.forename: P
authors.initials: P
authors.lastname: Gailly
authors.forename: C
authors.initials: C
authors.lastname: Vandier
authors.forename: R
authors.initials: R
authors.lastname: Kiss
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D054830:Sesterterpenes / Q000494:pharmacology*
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D054830:Sesterterpenes; C040764:ophiobolin A; D011188:Potassium
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