Jun 2, 2020

Small Molecule Intervention in a PKC-Gli Axis

ACS Chemical Biology
UyenPhuong TranAlison E Ondrus

Abstract

Aberrations in the Hedgehog 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 Gli oncogenes, 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 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.

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Mentioned in this Paper

Zinc Finger Protein GLI1
Hh Signaling Pathway
Malignant Neoplasms
Smo protein, mouse
GLI1 gene
Protein kinase C kinase
Insensitivity
SMO protein, human
Transcription Factor
Hedgehog Signaling Pathway

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