Cytostatic effect of TNFα on cancer cells is independent of p21WAF1

Abstract

Tumor necrosis factor a (TNFa) is a cytotoxic/cytostatic compound for a variety of human cancer cells. The p21 WAF1 protein is a cyclin-dependent kinase inhibitor (CDKI) that binds to cyclin/cyclin-dependent kinase (CDK) complexes and inhibits their kinase activities, thereby leading to cell cycle arrest. We found that the cytostatic eect of TNFa on the cervical cancer cell line, ME180, was concomitant with an arrest of these cells in the G0/G1 phase of the cell-cycle. This corresponded with an increase in both p21 WAF1 mRNA and protein levels which likely occurred via a p53-independent pathway since ME180 is infected with the human papilloma virus. To elucidate the role of p21 WAF1 in the TNFa-mediated growth and cell cycle arrest, we stably transformed ME180 cells with an antisense p21 WAF1 -expression vector. Two clones with reduced levels of p21 WAF1 both in their basal state as well as after their exposure to TNFa were selected. The growth of these cells was still inhibited by TNFa and they arrested in G0/G1 similar to wildtype or empty vector transfected cells. These results indicate that although p21 WAF1 expression increases dramatically with TNFa treatment, it may not play a critical role in the cytostatic eect of TNFa on ME180 cervical cancer cells.

Accumulation of an inactive form of p53 protein in cells treated with TNFα

“…In different cellular models, other investigators have found that p21/Waf1 is not required to induce G1-arrest in response to TNFa. Shiohara et al 51 have shown that overexpression of p21/Waf1 antisense in ME-180 cells does not abrogate TNFa-dependent G1-growth arrest. Additionally, Nalca and Rangnekar 52 have demonstrated that interleukin-1 (IL-1), another cytokine promoting cytostatic effects, induces p53 and p21/Waf1 expression.…”

PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation

“…6,25 In this study, U87 cells depleted of either p53 or p21 did not develop a senescent phenotype, but instead remained cytostatic as opposed to triggering apoptosis in response to activated AKT. 26,27 In addition, acute PTEN inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo. 28 PTEN/AKT might exert another regulatory function(s) of cell proliferation through a p53/p21-independent pathway.…”

Bacterial lipopolysaccharide enhances aflatoxin B1 hepatotoxicity in rats by a mechanism that depends on tumor necrosis factor α

“…Among these are both mitogenic and antimitogenic activities. [64][65][66] Cell division and tissue repair occur as events opposing injury and can limit the extent of liver injury. 36,37 That is, cell proliferation can afford protection whereas a lack of proliferation can increase injury.…”