PKC-mediated survival signaling in breast carcinoma cells: a role for MEK1-AP1 signaling.
The ability of peptide hormones, as well as the protein kinase C (PKC)-activating phorbol ester (PMA), to protect cells from apoptosis has been demonstrated to occur through activation of cellular signaling pathways such as the mitogen-activated protein kinase (MAPK) and phosphatidyl-inositol-3 kinase (PI3K) families. Here we demonstrate that tumor necrosis factor alpha (TNF)-induced apoptosis is suppressed by treatment with PMA in MCF-7 breast carcinoma cells. Reversal of the PMA survival effect with the classical isoform-specific PKC inhibitor, Go 6976, or the selective mitogen-activated protein kinase kinase (MEK) inhibitor, PD 098059, suggested a partial requirement for PKCalpha and the Erk cascade in MCF-7 cell survival. The ability of these agents to block PMA-mediated cell survival was also correlated with a suppression of PMA-induced AP-1 activity. Some naturally occurring flavonoid compounds such as apigenin can function to block cell signaling cascades such as MAPK. The ability of apigenin to block PMA-mediated cell survival was similarly correlated with suppression of PMA-stimulated AP-1 activity. Our results strongly suggest that PKC- and Erk-dependent pathways are critical components of the cell survival cascade function in suppression of TNF-induced apoptosis in MCF-7 cells. The ability of natural dietary flavonoids such as apigenin to affect cell survival pathways may represent an important aspect of the proposed anti-tumor effects of these compounds.
Weldon
Christopher B
CB
Department of Surgery, Tulane University School of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
McKee
Amy
A
Collins-Burow
Bridgette M
BM
Melnik
Lilia I
LI
Scandurro
Aline B
AB
McLachlan
John A
JA
Burow
Matthew E
ME
Beckman
Barbara S
BS
D047310:Apigenin / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D002470:Cell Survival; D004032:Diet; D005260:Female; D047309:Flavones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D047309:Flavones; D005419:Flavonoids; D010703:Phorbol Esters; D014409:Tumor Necrosis Factor-alpha; D047310:Apigenin; D011493:Protein Kinase C; D048369:MAP Kinase Kinase 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one