Chk1 inhibition activates p53 through p38 MAPK  in tetraploid cancer cells.
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.
Vitale
Ilio
I
INSERM, U848, Unit Apoptosis, Cancer and Immunity, Villejuif, France.
Senovilla
Laura
L
Galluzzi
Lorenzo
L
Criollo
Alfredo
A
Vivet
Sonia
S
Castedo
Maria
M
Kroemer
Guido
G
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010766:Phosphorylation; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C054852:7-hydroxystaurosporine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D019311:Staurosporine; C093642:SB 203580