Rottlerin: a multifaced regulator of keratinocyte cell cycle.
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.
Valacchi
Giuseppe
G
Department of Biomedical Sciences, University of Siena, Siena, Italy.
Pecorelli
Alessandra
A
Mencarelli
Marzia
M
Carbotti
Paola
P
Fortino
Vittoria
V
Muscettola
Michela
M
Maioli
Emanuela
E
D000098:Acetophenones / Q000494:pharmacology*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis; D056742:Cyclin D2; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D019940:Genes, bcl-1 / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
D000098:Acetophenones; D001578:Benzopyrans; C530104:CCND1 protein, human; C080336:CCND2 protein, human; C493956:CDKN1A protein, human; D056742:Cyclin D2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006131:Growth Inhibitors; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D019938:Cyclin D1; C085746:rottlerin; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases