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.

中文翻译：

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蛋白激酶 C-Gli 转录因子轴的小分子干预。

Hedgehog (Hh) 信号通路的异常是导致多种人类癌症的原因，但只有一个子集依赖于临床靶点 Smoothened (Smo) 的活性。新出现的对 Smo 靶向药物不敏感的癌症病例需要新的治疗靶点和抑制药物。因此，我们试图寻求最近发现的 Hedgehog 通路转录因子、胶质瘤相关癌基因同源物 (Glis) 和蛋白激酶 C (PKC) 同工酶之间的联系。在这里，我们报告了我们对结构多样化的 PKC 效应器库对 Gli 功能的影响的评估。使用在 Smo 上下游采用不同 Gli 激活机制的细胞系，我们确定了一种 PKC 效应器，它通过一种不依赖于有丝分裂原活化蛋白激酶激酶 (MEK) 的机制充当 Smo 下游的纳摩尔 Gli 拮抗剂。该试剂提供了一种独特的工具来阐明 PKC 同工酶和 Hh 信号之间的串扰，以及治疗干预 Hh 通路依赖性癌症的新机会。