Destruction of a Microtubule-Bound MYC Reservoir during Mitosis Contributes to Vincristine's Anticancer Activity.
Antineoplastic Agents, Phytogenic
/ pharmacology
Apoptosis
Biomarkers, Tumor
/ genetics
Cell Cycle
Cell Proliferation
Gene Expression Regulation, Neoplastic
Humans
Microtubules
/ metabolism
Mitosis
Neoplasms
/ drug therapy
Phosphorylation
Protein Binding
Proto-Oncogene Proteins c-myc
/ genetics
Tumor Cells, Cultured
Vincristine
/ pharmacology
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
14
12
2019
revised:
11
02
2020
accepted:
09
03
2020
pubmed:
13
3
2020
medline:
2
6
2021
entrez:
13
3
2020
Statut:
ppublish
Résumé
Tightly regulated activity of the transcription factor MYC is essential for orderly cell proliferation. Upon deregulation, MYC elicits and promotes cancer progression. Proteasomal degradation is an essential element of MYC regulation, initiated by phosphorylation at Serine62 (Ser62) of the MB1 region. Here, we found that Ser62 phosphorylation peaks in mitosis, but that a fraction of nonphosphorylated MYC binds to the microtubules of the mitotic spindle. Consequently, the microtubule-destabilizing drug vincristine decreases wild-type MYC stability, whereas phosphorylation-deficient MYC is more stable, contributing to vincristine resistance and induction of polyploidy. PI3K inhibition attenuates postmitotic MYC formation and augments the cytotoxic effect of vincristine. IMPLICATIONS: The spindle's function as a docking site for MYC during mitosis may constitute a window of specific vulnerability to be exploited for cancer treatment.
Identifiants
pubmed: 32161139
pii: 1541-7786.MCR-19-1203
doi: 10.1158/1541-7786.MCR-19-1203
doi:
Substances chimiques
Antineoplastic Agents, Phytogenic
0
Biomarkers, Tumor
0
MYC protein, human
0
Proto-Oncogene Proteins c-myc
0
Vincristine
5J49Q6B70F
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
859-872Informations de copyright
©2020 American Association for Cancer Research.