The microtubule targeting agent ST-401 triggers cell death in interphase and prevents the formation of polyploid giant cancer cells.
Humans
Interphase
/ drug effects
Microtubules
/ metabolism
Polyploidy
Cell Line, Tumor
Cell Death
/ drug effects
Giant Cells
/ drug effects
Mitochondrial Dynamics
/ drug effects
Energy Metabolism
/ drug effects
Glioblastoma
/ pathology
Neoplasms
/ pathology
Mitochondria
/ metabolism
Gene Expression Regulation, Neoplastic
/ drug effects
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
10 May 2024
10 May 2024
Historique:
received:
30
10
2023
accepted:
24
04
2024
medline:
11
5
2024
pubmed:
11
5
2024
entrez:
10
5
2024
Statut:
epublish
Résumé
Microtubule targeting agents (MTAs) are commonly prescribed to treat cancers and predominantly kill cancer cells in mitosis. Significantly, some MTA-treated cancer cells escape death in mitosis, exit mitosis and become malignant polyploid giant cancer cells (PGCC). Considering the low number of cancer cells undergoing mitosis in tumor tissues, killing them in interphase may represent a favored antitumor approach. We discovered that ST-401, a mild inhibitor of microtubule (MT) assembly, preferentially kills cancer cells in interphase as opposed to mitosis, a cell death mechanism that avoids the development of PGCC. Single cell RNA sequencing identified mRNA transcripts regulated by ST-401, including mRNAs involved in ribosome and mitochondrial functions. Accordingly, ST-401 induces a transient integrated stress response, reduces energy metabolism, and promotes mitochondria fission. This cell response may underly death in interphase and avoid the development of PGCC. Considering that ST-401 is a brain-penetrant MTA, we validated these results in glioblastoma cell lines and found that ST-401 also reduces energy metabolism and promotes mitochondria fission in GBM sensitive lines. Thus, brain-penetrant mild inhibitors of MT assembly, such as ST-401, that induce death in interphase through a previously unanticipated antitumor mechanism represent a potentially transformative new class of therapeutics for the treatment of GBM.
Identifiants
pubmed: 38730481
doi: 10.1186/s12967-024-05234-3
pii: 10.1186/s12967-024-05234-3
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
441Subventions
Organisme : NINDS NIH HHS
ID : NS106924
Pays : United States
Organisme : NCI NIH HHS
ID : CA244213
Pays : United States
Organisme : NIGMS NIH HHS
ID : GM069429
Pays : United States
Organisme : NIEHS NIH HHS
ID : DP2ES032761
Pays : United States
Informations de copyright
© 2024. The Author(s).
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