A prenylation inhibitor (sodium phenylacetate) differently affects MCF-7 cell death when ras is overexpressed, partly involving P42/44, JNK and P38 kinase activations.
BACKGROUND
Sodium phenylacetate (NaPa) inhibits breast cancer cell proliferation decreasing prenylation of small G proteins including Ras.


METHODS
Aponecrosis induced by NaPa in MCF-7 and MCF-7ras breast cancer cells was evaluated by measuring Annexin V/PI labelling by flow cytometry. Specific inhibitors of p42/44 (PD 98059), p38 (SB 600125) and JNK (SP 202190) in association with NaPa were also tested. Mitogen-activated kinase (MAPK) activation was measured by immunoprecipitation.


RESULTS
NaPa induced cell death more efficiently (80%) in the MCF-7ras cells compared to the MCF-7 cells (60%). NaPa activated ERK 1/2 and its combination with PD 98059 decreased cell death in the MCF-7ras cells in contrast to the MCF-7 cells. Combination of NaPa with specific inhibitors of both JNK and p38 kinases also partly decreased MCF-7ras cell death.


CONCLUSIONS
NaPa induced cell death differently when ras was overexpressed in breast cancer cells, partly involving p42/44, JNK and p38 pathways.
Laboratoire de Pharmaco-Oncologie Cellulaire, UMR-CNRS 7033, Paris, France. dibenedetto22@yahoo.fr
Mélanie
M
Di Benedetto
Michel
M
Crépin
Michel
M
Kraemer
Olivier
O
Oudar
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005419:Flavonoids / Q000494:pharmacology; D011905:Genes, ras; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010648:Phenylacetates / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D005419:Flavonoids; D010648:Phenylacetates; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); C025136:phenylacetic acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one