The microtubule targeting agents eribulin and paclitaxel activate similar signaling pathways and induce cell death predominantly in a caspase-independent manner.
Anthracenes
/ pharmacology
Butadienes
/ pharmacology
Caspase 3
/ metabolism
Cell Cycle
/ drug effects
Cell Death
/ drug effects
Cell Line, Tumor
Furans
/ pharmacology
Humans
Ketones
/ pharmacology
Microtubules
/ drug effects
Mitogen-Activated Protein Kinases
/ metabolism
Nitriles
/ pharmacology
Paclitaxel
/ pharmacology
Phosphorylation
/ drug effects
Proto-Oncogene Proteins c-bcl-2
/ metabolism
Signal Transduction
/ drug effects
Bcl-2 phosphorylation
MTA
cell death
microtubule
mitotic arrest
Journal
Cell cycle (Georgetown, Tex.)
ISSN: 1551-4005
Titre abrégé: Cell Cycle
Pays: United States
ID NLM: 101137841
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
pubmed:
22
1
2020
medline:
30
1
2021
entrez:
22
1
2020
Statut:
ppublish
Résumé
Microtubule-targeting agents (MTAs) are the most effective chemotherapeutics used in cancer therapy to date, but their clinical use is often hampered by the acquisition of resistance. Thereby, elucidation of the molecular signaling pathways activated by novel FDA-approved MTAs such as eribulin is important for future therapeutic applications. In contrast to several reports, we show here that regardless of the presence of caspase-3, clinically relevant concentrations of eribulin and the classical MTA paclitaxel predominantly induce caspase-independent cell death in MCF-7 breast carcinoma cells. On the molecular level, several key proteins involved in apoptosis such as p53, Plk1, caspase-2, and Bim as well as the two MAPKs ERK and JNK were activated by both compounds to a similar extent. However, none of them proved to be important for eribulin- and paclitaxel-induced cytotoxicity, as their siRNA-mediated knockdown or inactivation by small molecule inhibitors did not alter cell death rates. In contrast, knockdown of the anti-apoptotic Bcl-2 protein, which becomes heavily phosphorylated at Ser70 during MTA treatment, resulted surprisingly in a reduction of MTA-mediated cell death. This phenomenon can be most likely explained by our observation that the absence of Bcl-2 slowed down cell cycle progression resulting in fewer cells entering mitosis, thereby delaying the mitotic capability of these MTAs to induce cell death. Taken together, although eribulin and paclitaxel disturb the mitotic spindle differently, they exhibit no functional differences in downstream molecular cell death signaling in MCF-7 breast cancer cells.
Identifiants
pubmed: 31959066
doi: 10.1080/15384101.2020.1716144
pmc: PMC7100887
doi:
Substances chimiques
Anthracenes
0
Butadienes
0
Furans
0
Ketones
0
Nitriles
0
Proto-Oncogene Proteins c-bcl-2
0
U 0126
0
pyrazolanthrone
1TW30Y2766
Mitogen-Activated Protein Kinases
EC 2.7.11.24
Caspase 3
EC 3.4.22.-
eribulin
LR24G6354G
Paclitaxel
P88XT4IS4D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
464-478Références
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