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Pharmacological Perturbation of the Golgi Checkpoint Synergizes with Apoptotic Priming to Selectively Induce Tumor Cell Death.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Pharmacological Perturbation of the Golgi Checkpoint Synergizes with Apoptotic Priming to Selectively Induce Tumor Cell Death.
Συγγραφείς: Iannitti R; Institute of Endotypes in Oncology, Metabolism, and Immunology 'G. Salvatore' (IEOMI), Street Pietro Castellino 111, 80131 Naples, Italy., Colanzi A; Institute of Endotypes in Oncology, Metabolism, and Immunology 'G. Salvatore' (IEOMI), Street Pietro Castellino 111, 80131 Naples, Italy., Mascanzoni F; Institute of Endotypes in Oncology, Metabolism, and Immunology 'G. Salvatore' (IEOMI), Street Pietro Castellino 111, 80131 Naples, Italy.
Πηγή: Cells [Cells] 2026 Oct 07; Vol. 15 (19). Date of Electronic Publication: 2026 Oct 07.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE
Imprint Name(s): Original Publication: Basel, Switzerland : MDPI
Ιατρικοί όροι (MeSH): Golgi Apparatus*/drug effects , Golgi Apparatus*/metabolism , Apoptosis*/drug effects , Neoplasms*/pathology, Mitosis/drug effects ; Cell Proliferation/drug effects ; Humans ; Cell Line, Tumor
Περίληψη: Proper mitotic progression requires not only completion of DNA replication but also structural remodelling of the Golgi complex, including unlinking of the Golgi ribbon into isolated stacks during G2. This process activates a Golgi-dependent checkpoint that ensures accurate spindle assembly and cytokinesis. We previously showed that preventing GRASP65 phosphorylation through JNK inhibition blocks Golgi unlinking, impairs Aurora-A recruitment to centrosomes and, upon forced mitotic entry, induces multipolar spindles and binucleation. These studies established the mechanistic framework linking Golgi unlinking to mitotic entry and spindle formation. Here, building on this established framework, we asked whether the resulting mitotic vulnerability could be pharmacologically exploited. We therefore used SP600125 (SP) together with MK1775 (MK) as a previously characterized pharmacological platform and screened for compounds capable of further sensitizing these cells to death. This screen identified Navitoclax, a BCL-2/BCL-XL inhibitor, as the strongest enhancer of the SP+MK response. The triple combination selectively inhibited proliferation and induced apoptosis in tumor cells, while non-transformed RPE-1 cells remained largely resistant. Importantly, its activity depended on Golgi integrity: disrupting Golgi architecture with Brefeldin A partially restored cell viability, and efficacy correlated with Golgi compaction. Annexin V analysis confirmed apoptosis rather than mitotic slippage. Together, these findings identify a tumor-selective vulnerability linked to Golgi checkpoint disruption and support a therapeutic strategy combining Golgi checkpoint inhibition, forced mitotic entry and apoptotic priming to selectively eliminate cancer cells.
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Grant Information: 20095 AIRC Institute of Molecular Oncology
Contributed Indexing: Keywords: Golgi checkpoint; apoptotic priming; combinatorial drug strategy
Entry Date(s): Date Created: 20261016 Date Completed: 20261016 Latest Revision: 20261020
Update Code: 20261020
PubMed Central ID: PMC13664185
DOI: 10.3390/cells15191825
PMID: 42882523
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2073-4409
DOI:10.3390/cells15191825