Abstract
We have previously shown that tetraploid cancer cells succumb through a p53-dependent apoptotic pathway when checkpoint kinase 1 (Chk1) is depleted by small interfering RNAs (siRNAs) or inhibited with 7-hydroxystaurosporine (UCN-01). Here, we demonstrate that Chk1 inhibition results in the activating phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Depletion of p38 MAPK by transfection with a siRNA targeting the alpha isoform of p38 MAPK (p38alpha MAPK) abolishes the phosphorylation of p53 on serines 15 and 46 that is induced by Chk1 knockdown. The siRNA-mediated downregulation and pharmacological inhibition of p38alpha MAPK (with SB 203580) also reduces cell death induced by Chk1 knockdown or UCN-01. These results underscore the role of p38 MAPK as a pro-apoptotic kinase in the p53-dependant pathway for the therapeutic elimination of polyploidy cells.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents / pharmacology
-
Apoptosis / drug effects
-
Cell Line, Tumor
-
Checkpoint Kinase 1
-
Down-Regulation / drug effects
-
Enzyme Inhibitors / pharmacology
-
HCT116 Cells
-
Humans
-
Imidazoles / pharmacology
-
Phosphorylation
-
Polyploidy
-
Protein Kinase Inhibitors / pharmacology*
-
Protein Kinases / metabolism*
-
Pyridines / pharmacology
-
RNA, Small Interfering / metabolism
-
Staurosporine / analogs & derivatives
-
Staurosporine / pharmacology
-
Transfection
-
Tumor Suppressor Protein p53 / metabolism*
-
p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
-
Antineoplastic Agents
-
Enzyme Inhibitors
-
Imidazoles
-
Protein Kinase Inhibitors
-
Pyridines
-
RNA, Small Interfering
-
Tumor Suppressor Protein p53
-
7-hydroxystaurosporine
-
Protein Kinases
-
CHEK1 protein, human
-
Checkpoint Kinase 1
-
p38 Mitogen-Activated Protein Kinases
-
Staurosporine
-
SB 203580