Prevention of tumor necrosis factor (TNF)-mediated induction of p21 (WAF1/CIP1) sensitizes MCF-7 carcinoma cells to TNF-induced apoptosis

Abstract

The MCF-7 breast carcinoma and MRC-5 lung fibroblast cell lines are sensitive and resistant to tumor necrosis factor (TNF)-induced apoptosis, respectively. As the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is involved in cell cycle regulation and has been implicated in apoptosis, we studied the influence of p21 on growth of MRC-5 cells and on growth and apoptosis in MCF-7 cells. TNF induced p21 mRNA and protein in both cell types, p21 induction by > 0.5 ng/ml TNF in MRC-5 and MCF-7 cells correlated with the inhibition of cell growth. In contrast, < 0.1 ng/ml TNF stimulated MRC-5 (but not MCF-7) cell growth without reduction in p21 levels. TNF-induced apoptosis in MCF-7 cells was first detected after the TNF-mediated increase in p21 and growth arrest had occurred. MCF-7 cells stably transfected with antisense p21 cDNA became more sensitive to TNF-induced apoptosis. Thus, TNF-induced p21 accompanied by growth arrest may counteract or delay TNF cytotoxicity in MCF-7 cells.