Department of Chemistry and Biochemistry, California State University Fullerton, 800 N State College Blvd, Fullerton, California 92831, United States.
Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena, California 91125, United States.
ACS Chem Biol. 2020 Jun 19;15(6):1321-1327. doi: 10.1021/acschembio.0c00355. Epub 2020 Jun 8.
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.
Hedgehog (Hh) 信号通路的异常与广泛的人类癌症有关，但只有一部分依赖于临床靶点 Smoothened (Smo) 的活性。越来越多的对 Smo 靶向药物不敏感的癌症病例需要新的治疗靶点和抑制剂。因此，我们试图探索 Hedgehog 通路转录因子Glioma-associated oncogene homologues (Glis) 和蛋白激酶 C (PKC) 同工酶之间最近发现的联系。在这里，我们报告了对结构多样的 PKC 效应物文库的评估，以了解它们对 Gli 功能的影响。我们使用 Smo 上下游采用不同 Gli 激活机制的细胞系，鉴定出一种 PKC 效应物，它通过丝裂原活化蛋白激酶激酶 (MEK) 独立机制，作为 Smo 下游的纳摩尔Gli 拮抗剂发挥作用。该试剂为阐明 PKC 同工酶与 Hh 信号转导之间的串扰提供了独特的工具，并为 Hh 通路依赖性癌症的治疗干预提供了新的机会。
