Concomitant targeting of Hedgehog signaling and MCL-1 synergistically induces cell death in Hedgehog-driven cancer cells.
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Drug Synergism
Gene Expression Regulation, Neoplastic
/ drug effects
Hedgehog Proteins
/ metabolism
Humans
Indoles
/ pharmacology
Mitochondria
/ drug effects
Myeloid Cell Leukemia Sequence 1 Protein
/ metabolism
Neoplasms
/ drug therapy
Pyridines
/ pharmacology
Pyrimidines
/ pharmacology
Signal Transduction
/ drug effects
Sulfonamides
/ pharmacology
Zinc Finger Protein GLI1
/ metabolism
A-1210477
BIM
GANT61
Hedgehog signaling
MCL-1
NOXA
Rhabdomyosarcoma
Journal
Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053
Informations de publication
Date de publication:
28 Nov 2019
28 Nov 2019
Historique:
received:
04
07
2019
revised:
21
08
2019
accepted:
23
08
2019
pubmed:
30
8
2019
medline:
23
5
2020
entrez:
30
8
2019
Statut:
ppublish
Résumé
In the present study, we show that concomitant inhibition of Hedgehog (HH) signaling by the glioma-associated oncogene homolog1 (GLI1)-targeting agent GANT61 and the antiapoptotic BCL-2 protein family member MCL-1 by A-1210477 synergistically induces cell death in HH-driven cancers, i.e. rhabdomyosarcoma (RMS) and medulloblastoma (MB) cells. Combined genetic and pharmacological inhibition emphasized that co-treatment of GANT61 and A-1210477 indeed relies on inhibition of GLI1 (by GANT61) and MCL-1 (by A-1210477). Mechanistic studies revealed that A-1210477 triggers the release of BIM from MCL-1 and its shuttling to BCL-x
Identifiants
pubmed: 31465840
pii: S0304-3835(19)30449-5
doi: 10.1016/j.canlet.2019.08.012
pii:
doi:
Substances chimiques
A-1210477
0
GANT 61
0
GLI1 protein, human
0
Hedgehog Proteins
0
Indoles
0
MCL1 protein, human
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Pyridines
0
Pyrimidines
0
Sulfonamides
0
Zinc Finger Protein GLI1
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1-11Informations de copyright
Copyright © 2019. Published by Elsevier B.V.