Thiostrepton induces spindle abnormalities and enhances Taxol cytotoxicity in MDA-MB-231 cells.
Humans
Paclitaxel
/ pharmacology
Thiostrepton
/ pharmacology
Cell Line, Tumor
Spindle Apparatus
/ drug effects
Forkhead Box Protein M1
/ metabolism
Autophagy
/ drug effects
Tubulin
/ metabolism
Apoptosis
/ drug effects
Triple Negative Breast Neoplasms
/ drug therapy
Female
Drug Synergism
Microtubules
/ metabolism
Mitosis
/ drug effects
HSP70 Heat-Shock Proteins
/ metabolism
MDA-MB-231 Cells
Cell death
Mitotic spindle assembly
Taxol
Thiostrepton
Tubulin polymerization
Journal
Molecular biology reports
ISSN: 1573-4978
Titre abrégé: Mol Biol Rep
Pays: Netherlands
ID NLM: 0403234
Informations de publication
Date de publication:
21 Aug 2024
21 Aug 2024
Historique:
received:
16
04
2024
accepted:
14
08
2024
medline:
22
8
2024
pubmed:
22
8
2024
entrez:
21
8
2024
Statut:
epublish
Résumé
Thiostrepton (TST) is a known inhibitor of the transcription factor Forkhead box M1 (FoxM1) and inducer of heat shock response (HSR) and autophagy. TST thus may be one potential candidate of anticancer drugs for combination chemotherapy. Immunofluorescence staining of mitotic spindles and flow cytometry analysis revealed that TST induces mitotic spindle abnormalities, mitotic arrest, and apoptotic cell death in the MDA-MB-231 triple-negative breast cancer cell line. Interestingly, overexpression or depletion of FoxM1 in MDA-MB-231 cells did not affect TST induction of spindle abnormalities; however, TST-induced spindle defects were enhanced by inhibition of HSP70 or autophagy. Moreover, TST exhibited low affinity for tubulin and only slightly inhibited in vitro tubulin polymerization, but it severely impeded tubulin polymerization and destabilized microtubules in arrested mitotic MDA-MB-231 cells. Additionally, TST significantly enhanced Taxol cytotoxicity. TST also caused cytotoxicity and spindle abnormalities in a Taxol-resistant cell line, MDA-MB-231-T4R. These results suggest that, in addition to inhibiting FoxM1, TST may induce proteotoxicity and autophagy to disrupt cellular tubulin polymerization, and this mechanism might account for its antimitotic effects, enhancement of Taxol anticancer effects, and ability to overcome Taxol resistance in MDA-MB-231 cells. These data further imply that TST may be useful to improve the therapeutic efficacy of Taxol.
Sections du résumé
BACKGROUND
BACKGROUND
Thiostrepton (TST) is a known inhibitor of the transcription factor Forkhead box M1 (FoxM1) and inducer of heat shock response (HSR) and autophagy. TST thus may be one potential candidate of anticancer drugs for combination chemotherapy.
METHODS AND RESULTS
RESULTS
Immunofluorescence staining of mitotic spindles and flow cytometry analysis revealed that TST induces mitotic spindle abnormalities, mitotic arrest, and apoptotic cell death in the MDA-MB-231 triple-negative breast cancer cell line. Interestingly, overexpression or depletion of FoxM1 in MDA-MB-231 cells did not affect TST induction of spindle abnormalities; however, TST-induced spindle defects were enhanced by inhibition of HSP70 or autophagy. Moreover, TST exhibited low affinity for tubulin and only slightly inhibited in vitro tubulin polymerization, but it severely impeded tubulin polymerization and destabilized microtubules in arrested mitotic MDA-MB-231 cells. Additionally, TST significantly enhanced Taxol cytotoxicity. TST also caused cytotoxicity and spindle abnormalities in a Taxol-resistant cell line, MDA-MB-231-T4R.
CONCLUSIONS
CONCLUSIONS
These results suggest that, in addition to inhibiting FoxM1, TST may induce proteotoxicity and autophagy to disrupt cellular tubulin polymerization, and this mechanism might account for its antimitotic effects, enhancement of Taxol anticancer effects, and ability to overcome Taxol resistance in MDA-MB-231 cells. These data further imply that TST may be useful to improve the therapeutic efficacy of Taxol.
Identifiants
pubmed: 39168955
doi: 10.1007/s11033-024-09863-1
pii: 10.1007/s11033-024-09863-1
doi:
Substances chimiques
Paclitaxel
P88XT4IS4D
Thiostrepton
HR4S203Y18
Forkhead Box Protein M1
0
FOXM1 protein, human
0
Tubulin
0
HSP70 Heat-Shock Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
927Subventions
Organisme : National Science and Technology Council
ID : MOST 111-2320-B-001 -011 -MY3
Informations de copyright
© 2024. The Author(s).
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