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GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas

Scott X Atwood1, Mischa Li, Alex Lee

  • 1Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.

Nature
|March 1, 2013
PubMed

Insights

Atypical protein kinase C ι/λ (aPKC-ι/λ) is a novel regulator of hedgehog (HH) signalling, crucial for basal cell carcinoma (BCC) growth. Targeting aPKC-ι/λ offers a new therapeutic strategy for SMO-inhibitor-resistant BCCs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signalling

Background:

  • Basal cell carcinomas (BCCs) rely on hedgehog (HH) signalling via GLI transcription factors for growth.
  • Smoothened (SMO) inhibitors are used to suppress HH signalling, but tumour resistance necessitates new therapeutic targets.

Purpose of the Study:

  • To identify novel regulators of GLI transcription factors downstream of SMO.
  • To investigate the role of atypical protein kinase C ι/λ (aPKC-ι/λ) in HH signalling and BCC proliferation.
  • To evaluate aPKC-ι/λ as a potential therapeutic target for SMO-inhibitor-resistant cancers.

Main Methods:

  • Genetic and pharmacological inhibition of aPKC-ι/λ.
  • Co-localization studies at the centrosome with MIM.
  • Genome-wide transcriptional profiling.
  • Analysis of aPKC-ι/λ expression in SMO-inhibitor-resistant BCCs.

Main Results:

  • aPKC-ι/λ acts downstream of SMO to phosphorylate and activate GLI1, enhancing DNA binding and transcription.
  • Loss of aPKC-ι/λ function inhibits HH signalling and BCC cell proliferation.
  • Activated aPKC-ι/λ is upregulated in SMO-inhibitor-resistant tumours.
  • Targeting aPKC-ι/λ suppresses the growth of resistant BCC cell lines.

Conclusions:

  • aPKC-ι/λ is a critical regulator of HH-dependent processes and GLI activation in mammals.
  • aPKC-ι/λ represents a novel, tumour-selective therapeutic target for SMO-inhibitor-resistant cancers.

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