Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine

Nature. 2000 Aug 31;406(6799):1005-9. doi: 10.1038/35023008.

Abstract

Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma and other human tumours are associated with mutations that activate the proto-oncogene Smoothened (SMO) or that inactivate the tumour suppressor Patched (PTCH). Smoothened and Patched mediate the cellular response to the Hedgehog (Hh) secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the Hh response pathway. Here we show that the plant-derived teratogen cyclopamine, which inhibits the Hh response, is a potential 'mechanism-based' therapeutic agent for treatment of these tumours. We show that cyclopamine or synthetic derivatives with improved potency block activation of the Hh response pathway and abnormal cell growth associated with both types of oncogenic mutation. Our results also indicate that cyclopamine may act by influencing the balance between active and inactive forms of Smoothened.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Basal Cell Nevus Syndrome / drug therapy
  • Basal Cell Nevus Syndrome / genetics
  • Basal Cell Nevus Syndrome / metabolism
  • Cell Line
  • Cell Transformation, Neoplastic / drug effects
  • Cloning, Molecular
  • Drosophila
  • Drosophila Proteins*
  • Gene Expression Regulation / drug effects
  • Hedgehog Proteins
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mutation
  • Oncogenes
  • Patched Receptors
  • Patched-1 Receptor
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled*
  • Signal Transduction / drug effects*
  • Smoothened Receptor
  • Trans-Activators*
  • Veratrum Alkaloids / chemistry
  • Veratrum Alkaloids / pharmacology*

Substances

  • Antineoplastic Agents, Phytogenic
  • Drosophila Proteins
  • Hedgehog Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • PTCH protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Proteins
  • Ptch1 protein, mouse
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • SMO protein, human
  • Smo protein, mouse
  • Smoothened Receptor
  • Trans-Activators
  • Veratrum Alkaloids
  • smo protein, Drosophila
  • cyclopamine