Pyrvinium attenuates Hedgehog signaling downstream of smoothened. Academic Article uri icon

Overview

MeSH

  • Animals
  • Carcinoma, Basal Cell
  • Casein Kinase Ialpha
  • Cell Line
  • HEK293 Cells
  • Humans
  • Medulloblastoma
  • Mice
  • Mice, Nude
  • NIH 3T3 Cells
  • Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • Trans-Activators
  • Transcription Factors
  • Zinc Finger Protein GLI1

MeSH Major

  • Hedgehog Proteins
  • Pyrvinium Compounds
  • Signal Transduction

abstract

  • The Hedgehog (HH) signaling pathway represents an important class of emerging developmental signaling pathways that play critical roles in the genesis of a large number of human cancers. The pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), a key signaling effector of the HH pathway that regulates the levels and activity of the Gli family of transcription factors. Although one of these compounds, vismodegib, is now FDA-approved for patients with advanced basal cell carcinoma, acquired mutations in Smo can result in rapid relapse. Furthermore, many cancers also exhibit a Smo-independent activation of Gli proteins, an observation that may underlie the limited efficacy of Smo inhibitors in clinical trials against other types of cancer. Thus, there remains a critical need for HH inhibitors with different mechanisms of action, particularly those that act downstream of Smo. Recently, we identified the FDA-approved anti-pinworm compound pyrvinium as a novel, potent (IC50, 10 nmol/L) casein kinase-1α (CK1α) agonist. We show here that pyrvinium is a potent inhibitor of HH signaling, which acts by reducing the stability of the Gli family of transcription factors. Consistent with CK1α agonists acting on these most distal components of the HH signaling pathway, pyrvinium is able to inhibit the activity of a clinically relevant, vismodegib -resistant Smo mutant, as well as the Gli activity resulting from loss of the negative regulator suppressor of fused. We go on to demonstrate the utility of this small molecule in vivo, against the HH-dependent cancer medulloblastoma, attenuating its growth and reducing the expression of HH biomarkers. ©2014 American Association for Cancer Research.

publication date

  • September 1, 2014

has subject area

  • Animals
  • Carcinoma, Basal Cell
  • Casein Kinase Ialpha
  • Cell Line
  • HEK293 Cells
  • Hedgehog Proteins
  • Humans
  • Medulloblastoma
  • Mice
  • Mice, Nude
  • NIH 3T3 Cells
  • Oncogene Proteins
  • Pyrvinium Compounds
  • Receptors, G-Protein-Coupled
  • Signal Transduction
  • Trans-Activators
  • Transcription Factors
  • Zinc Finger Protein GLI1

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4321822

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-14-0317

PubMed ID

  • 24994715

Additional Document Info

start page

  • 4811

end page

  • 4821

volume

  • 74

number

  • 17