Small Molecule Intervention in a Protein Kinase C–Gli Transcription Factor Axis
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.
Additional Information
© 2020 American Chemical Society. Received: May 6, 2020; Accepted: June 1, 2020; Published: June 1, 2020. We thank J. K. Chen (Stanford University) for Shh-LIGHT2, Sufu-KO-LIGHT, C3H10T1/2, and TM3-Gli-Luc cells and S. X. Atwood (UC Irvine) for ASZ001 mBCC cells. We thank N. V. Patel (CSU Fullerton) for use of a GloMax luminometer. G.C.Z. was supported through a training grant (NIH GM07616) provided by the National Institutes of Health. This research was supported by start up funds granted by the College of Natural Sciences and Mathematics at California State University, Fullerton (K.L.B.), and the Division of Chemistry and Chemical Engineering at the California Institute of Technology (A.E.O.). The authors declare no competing financial interest.Attached Files
Accepted Version - nihms-1775724.pdf
Supplemental Material - cb0c00355_si_001.pdf
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Additional details
- Alternative title
- Small Molecule Intervention in a PKC-Gli Axis
- PMCID
- PMC8842554
- Eprint ID
- 103627
- Resolver ID
- CaltechAUTHORS:20200602-071011767
- GM07616
- NIH Predoctoral Fellowship
- California State University, Fullerton
- Caltech Division of Chemistry and Chemical Engineering
- Created
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2020-06-02Created from EPrint's datestamp field
- Updated
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2023-07-17Created from EPrint's last_modified field