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Small Molecule Intervention in a Protein Kinase C–Gli Transcription Factor Axis

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journal contribution
posted on 08.06.2020, 13:37 by UyenPhuong Tran, Grace C. Zhang, Ryan Eom, Kelvin L. Billingsley, Alison E. Ondrus
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.