Association of apoptosis with the inhibition of extracellular signal–regulated protein kinase activity in the tumor necrosis factor α-resistant ovarian carcinoma cell line UCI 101
✍ Scribed by Eugenia M. Yazlovitskaya; Jill C. Pelling; Diane L. Persons
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 201 KB
- Volume
- 25
- Category
- Article
- ISSN
- 0899-1987
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✦ Synopsis
Tumor necrosis factor-α (TNFα) can function as both an autocrine and a paracrine growth factor and may therefore play a role in ovarian tumor progression. TNFα initiates multiple cellular responses, many of which are mediated through the mitogen-activated protein kinase pathways, which transduce signals from the TNFα receptors through the cytoplasm to the nucleus, resulting in regulation of gene expression. We examined the role of c-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated protein kinase (ERK) 1 and 2 in the cellular growth response to TNFα in the ovarian carcinoma cell line UCI 101. JNK1 activity was increased to a maximum level ninefold above the basal level after 10-20 min of treatment with 10 ng/mL TNFα. A maximum threefold induction of ERK1/2 activity was observed after 1 min of treatment. At concentrations up to 100 ng/ mL, TNFα had neither a stimulatory nor an inhibitory effect on growth of UCI 101 cells. However, inhibition of TNFα-induced ERK1/2 activity by the MAP/ERK kinase 1 inhibitor PD 98059 resulted in 60% inhibition of cell growth in TNFα-treated UCI 101 cells. This decrease in cell growth was accompanied by apoptosis, as demonstrated by the presence of a 180-bp DNA ladder. Thus, the inhibition of TNFα-induced ERK1/2 activity was associated with induction of apoptosis in the TNFα-resistant cell line UCI 101. Inhibition of TNFα-induced ERK1/2 activity was accompanied by a subsequent transient increase in TNFα-induced JNK1 activity. The significance of this increase with respect to apoptosis induction remains to be determined. These findings demonstrated that ERK1/2 activity can modulate cellular sensitivity to TNFα and suggested that the balance between the levels of ERK1/2 and JNK1 activation may be critical in the cellular growth response to TNFα.