Abstract
Cyclopentenone prostaglandin derivatives of arachidonic acid are potent inducers of apoptosis in a variety of cancer cell types. Several investigators have shown that the terminal derivative of prostaglandin J(2) (PGJ(2)) metabolism, 15-deoxy-Delta(12,14)-PGJ(2) (15dPGJ(2)), induces apoptosis in breast cancer cells and is a potent activator of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma), but 15dPGJ(2) effects can be mediated by PPARgamma-dependent and PPARgamma-independent mechanisms. Here we report that 15dPGJ(2) regulates early gene expression critical to apoptosis. Specifically, 15dPGJ(2) induces potent and irreversible S phase arrest that is correlated with expression of genes critical to cell cycle arrest and apoptosis, including the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) (p21). Inhibition of RNA or protein synthesis abrogates apoptosis induced by 15dPGJ(2) in breast cancer cells but potentiates apoptosis induced by tumor necrosis factor-alpha or CD95/Fas ligand. Additionally, 15dPGJ(2) induces caspase activation that is blocked by peptide caspase inhibitors. These data show that de novo gene transcription is necessary for 15dPGJ(2)-induced apoptosis in breast cancer cells. Critical candidate genes are likely to be revealed through analysis of differential cDNA array expression.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Apoptosis* / drug effects
-
Blotting, Northern
-
Blotting, Western
-
Breast Neoplasms / drug therapy*
-
Breast Neoplasms / enzymology
-
Breast Neoplasms / genetics
-
Caspases / metabolism
-
Cyclin-Dependent Kinase Inhibitor p21
-
Cyclins / metabolism
-
Cycloheximide / pharmacology
-
DNA, Complementary / metabolism
-
Dactinomycin / pharmacology
-
Down-Regulation
-
Enzyme Activation
-
Flow Cytometry
-
Gene Expression Profiling
-
Gene Expression Regulation, Neoplastic*
-
Humans
-
Immunohistochemistry
-
Immunologic Factors / pharmacology*
-
Ligands
-
Microscopy, Fluorescence
-
Nucleic Acid Synthesis Inhibitors / pharmacology
-
Oligonucleotide Array Sequence Analysis
-
Prostaglandin D2 / analogs & derivatives*
-
Prostaglandin D2 / pharmacology*
-
Protein Synthesis Inhibitors / pharmacology
-
Receptors, Cytoplasmic and Nuclear / metabolism
-
S Phase / drug effects
-
Time Factors
-
Transcription Factors / metabolism
-
Transcription, Genetic
-
Tumor Cells, Cultured
-
Tumor Necrosis Factor-alpha / metabolism
-
Up-Regulation
Substances
-
15-deoxy-delta(12,14)-prostaglandin J2
-
CDKN1A protein, human
-
Cyclin-Dependent Kinase Inhibitor p21
-
Cyclins
-
DNA, Complementary
-
Immunologic Factors
-
Ligands
-
Nucleic Acid Synthesis Inhibitors
-
Protein Synthesis Inhibitors
-
Receptors, Cytoplasmic and Nuclear
-
Transcription Factors
-
Tumor Necrosis Factor-alpha
-
Dactinomycin
-
Cycloheximide
-
Caspases
-
Prostaglandin D2