Rottlerin: a multifaced regulator of keratinocyte cell cycle

Exp Dermatol. 2009 Jun;18(6):516-21. doi: 10.1111/j.1600-0625.2008.00816.x.

Abstract

In this study we showed that Rottlerin (also called Kamala or Mallotoxin), a natural product purified from Mallotus phillippinensis, is a potent suppressor of human keratinocytes (HaCaT cell line) proliferation. Following Rottlerin treatment, Thymidine incorporation into DNA and re-epithelialisation in a scratch wound model was decreased. At the molecular level, Rottlerin hampered the NFkB activation process, causing loss of cyclin D1 and promoting, in a PKCdelta-dependent pathway, ERK activation, which, in turn induced the cell cycle inhibitor p21 Cip1/Kip1. The NFkB-dependent drop in cyclin D1, along with the PKCdelta/ERK-dependent induction of p21 Cip1/Kip1, is responsible for growth arrest. These results open the way to further investigation on the Rottlerin therapeutic potential against keratinocyte hyper-proliferative disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology*
  • Active Transport, Cell Nucleus / drug effects
  • Benzopyrans / pharmacology*
  • Cell Cycle / drug effects
  • Cell Line, Transformed / drug effects
  • Cells, Cultured / cytology
  • Cells, Cultured / drug effects
  • Cyclin D1 / biosynthesis
  • Cyclin D2
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclins / biosynthesis
  • Cyclins / genetics
  • Drug Evaluation, Preclinical
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation / drug effects
  • Genes, bcl-1 / drug effects
  • Growth Inhibitors / pharmacology*
  • Humans
  • In Vitro Techniques
  • Keratinocytes / cytology
  • Keratinocytes / drug effects*
  • NF-kappa B / antagonists & inhibitors
  • Phosphorylation / drug effects
  • Protein Kinase C-delta / antagonists & inhibitors
  • Protein Kinase C-delta / physiology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Processing, Post-Translational / drug effects
  • Wound Healing / drug effects

Substances

  • Acetophenones
  • Benzopyrans
  • CCND1 protein, human
  • CCND2 protein, human
  • CDKN1A protein, human
  • Cyclin D2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Growth Inhibitors
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Cyclin D1
  • rottlerin
  • Protein Kinase C-delta
  • Extracellular Signal-Regulated MAP Kinases