Association of apoptosis with the inhibition of extracellular signal-regulated protein kinase activity in the tumor necrosis factor alpha-resistant ovarian carcinoma cell line UCI 101

Tumor necrosis factor-alpha (TNF alpha) can function as both an autocrine a nd a paracrine growth factor and may therefore play a role in ovarian tumor progression. TNF alpha initiates multiple cellular responses, many of whic h are mediated through the mitogen-activated protein kinase pathways, which transduce signals from the TNF alpha receptors through the cytoplasm to th e nucleus, resulting in regulation of gene expression. We examined the role of c-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated pro tein kinase (ERK) 1 and 2 in the cellular growth response to TNF alpha. in the ovarian carcinoma cell line UCI 101. JNK1 activity was increased to a m aximum level ninefold above the basal level after 10-20 min of treatment wi th 10 ng/mL TNF alpha. A maxim um threefold induction of ERK1/2 activity wa s observed after 1 min of treatment. At concentrations up to 100 ng/mL TNF alpha had neither a stimulatory nor an inhibitory effect on growth of UCI 1 01 cells. However, inhibition of TNF alpha-induced ERK1/2 activity by the M AP/ERK kinase 1 inhibitor PD 98059 resulted in 60% inhibition of cell growt h in TNF alpha-treated UCI 101 cells. This decrease in cell growth was acco mpanied by apoptosis, as demonstrated by the presence of a 180-bp DNA ladde r. Thus, the inhibition of TNF alpha-induced ERK1/2 activity was associated with induction of apoptosis in the TNF alpha-resistant cell line UCI 101. Inhibition of TNF alpha-induced ERK1/2 activity was accompanied by a subseq uent transient increase in TNF alpha-induced JNK1 activity. The significanc e of this increase with respect to apoptosis induction remains to be determ ined. These findings demonstrated that ERK1/2 activity can modulate cellula r sensitivity to TNF alpha and suggested that the balance between the level s of ERK1/2 and JNK1 activation may be critical in the cellular growth resp onse to TNF alpha. (C) 1999 Wiley-Liss, Inc.