Small Molecule Intervention in a Protein Kinase C-Gli Transcription Factor Axis.
ACS Chem Biol
; 15(6): 1321-1327, 2020 06 19.
Article
en En
| MEDLINE
| ID: mdl-32479053
ABSTRACT
Aberrations in the Hedgehog (Hh) signaling pathway are responsible for a broad range of human cancers, yet only a subset rely on the activity of the clinical target, Smoothened (Smo). Emerging cases of cancers that are insensitive to Smo-targeting drugs demand new therapeutic targets and agents for inhibition. As such, we sought to pursue a recently discovered connection between the Hedgehog pathway transcription factors, the glioma-associated oncogene homologues (Glis), and protein kinase C (PKC) isozymes. Here, we report our assessment of a structurally diverse library of PKC effectors for their influence on Gli function. Using cell lines that employ distinct mechanisms of Gli activation up- and downstream of Smo, we identify a PKC effector that acts as a nanomolar Gli antagonist downstream of Smo through a mitogen-activated protein kinase kinase (MEK)-independent mechanism. This agent provides a unique tool to illuminate crosstalk between PKC isozymes and Hh signaling and new opportunities for therapeutic intervention in Hh pathway-dependent cancers.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteína Quinasa C
/
Transducción de Señal
/
Bibliotecas de Moléculas Pequeñas
/
Proteína con Dedos de Zinc GLI1
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
ACS Chem Biol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos