Phorbol esters induce death in MCF-7 breast cancer cells with altered expression of protein kinase C isoforms. Role for p53-independent induction of gadd-45 in initiating death.
Protein kinase C (PKC) modulates growth, differentiation and apoptosis in a cell-specific fashion. Overexpression of PKC-alpha in MCF-7 breast cancer cells (MCF-7-PKC-alpha cell) leads to expression of a more transformed phenotype. The response of MCF-7 and MCF-7-PKC-alpha cells to phorbol esters (TPA) was examined. TPA-treated MCF-7 cells demonstrated a modest cytostatic response associated with a G1 arrest that was accompanied by Cip1 expression and retinoblastoma hypophosphorylation. While p53 was detected in MCF-7 cells, evidence for TPA-induced stimulation of p53 transcriptional activity was not evident. In contrast, TPA treatment induced death of MCF-7-PKC-alpha cells. Bryostatin 1, another PKC activator, exerted modest cytostatic effects on MCF-7 cells while producing a cytotoxic response at low doses in MCF-7-PKC-alpha cells that waned at higher concentrations. TPA-treated MCF-7-PKC-alpha cells accumulated in G2/M, did not express p53, displayed decreased Cip1 expression, and demonstrated a reduction in retinoblastoma hypophosphorylation. TPA-treated MCF-7-PKC-alpha cells expressed gadd-45 which occurred before the onset of apoptosis. Thus, alterations in the PKC pathway can modulate the decision of a breast cancer cell to undergo death or differentiation. In addition, these data show that PKC activation can induce expression of gadd45 in a p53-independent fashion.
de Vente
J E
JE
Department of Medicine, East Carolina University School of Medicine, Greenville, North Carolina 27858, USA.
Kukoly
C A
CA
Bryant
W O
WO
Posekany
K J
KJ
Chen
J
J
Fletcher
D J
DJ
Parker
P J
PJ
Pettit
G J
GJ
Lozano
G
G
Cook
P P
PP
D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology; D054713:Bryostatins; D002453:Cell Cycle / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000032:analysis*; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D010766:Phosphorylation; D011493:Protein Kinase C / Q000032:analysis*; D011506:Proteins / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D054713:Bryostatins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D007783:Lactones; D018942:Macrolides; D011493:Protein Kinase C; D011506:Proteins; D016160:Retinoblastoma Protein; D013755:Tetradecanoylphorbol Acetate; D000097642:GADD45 Proteins; C493956:CDKN1A protein, human; C046785:bryostatin 1