title: GSI promotes vincristine-induced apoptosis by enhancing multi-polar spindle formation.
abstract: Gamma secretase inhibitors (GSI), cell-permeable small-molecule inhibitors of gamma secretase activity, had been originally developed for the treatment of Alzheimer disease. In recent years, it has been exploited in cancer research to inhibit Notch signaling that is aberrantly activated in various cancers. We previously found that GSI could synergize with anti-microtubule agent, vincristine (VCR) in a Notch-independent manner. Here, we delineate the underlying cell cycle-related mechanism using HeLa cells, which have strong mitotic checkpoints. GSI enhanced VCR-induced cell death, although GSI alone did not affect cell viability at all. GSI augmented VCR-induced mitotic arrest in a dose-dependent manner, which was preceded by apoptotic cell death, as shown by an increase in Annexin V-positive and caspase-positive cell population. Furthermore, GSI amplified multi-polar spindle formation triggered by VCR. Altogether, we show the evidence that GSI enhances VCR-induced apoptosis in HeLa cells via multi-polar mitotic spindle formation, independent of Notch signaling. These data suggest that one or more GS substrates, yet to be identified, in a post-GS processed form, may play a role in maintaining functional centrosomes/mitotic spindles. More significantly, the synergistic effect of GSI in combination with VCR could be exploited in clinical setting to improve the efficacy of VCR.
authors.affiliation: Laboratory of Cellular Immunology; Ochsner Clinic Foundation; New Orleans, LA USA.
authors.forename: Akannsha
authors.initials: A
authors.lastname: Singh
authors.affiliation: Laboratory of Cellular Immunology; Ochsner Clinic Foundation; New Orleans, LA USA.
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Zapata
authors.affiliation: Laboratory of Cellular Immunology; Ochsner Clinic Foundation; New Orleans, LA USA.
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Laboratory of Cellular Immunology; Ochsner Clinic Foundation; New Orleans, LA USA.
authors.forename: Sun-Ok
authors.initials: SO
authors.lastname: Yoon
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D051880:Receptors, Notch / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D008941:Spindle Apparatus / Q000187:drug effects*; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D009842:Oligopeptides; D051880:Receptors, Notch; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D014750:Vincristine; D053829:Amyloid Precursor Protein Secretases
keywords: Notch; Vincristine; apoptosis; centrosome; gamma secretase inhibitor; mitotic arrest; multi-polar spindle; spindle assembly checkpoint