Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

Abstract

The CDK inhibitor p21 waf is a principal mediator of p53 function but can also be transactivated by many p53-independent stimuli leading to cell growth arrest or di erentiation. In order to study the function of p21 waf in a p53-de®cient environment, we established an inducible expression of p21 waf in the p53-null lung cancer cell line H1299, based on the muristerone-regulated system. Overexpression of p21 waf led cells to growth arrest which after several days became irreversible and the arrested cells acquired a senescent phenotype as judged by cell shape, the senescence-associated b-gal marker and inhibition of colony formation. The e ect of p21 waf overexpression, in the absence of p53, on the cytotoxicity caused by irradiation, doxorubicin and taxol was studied. Expression of p21 waf provided protection against the cytotoxic e ect of radiation and doxorubicin but not of taxol. These results are relevant to treatment of cancer when p53 is inactive.

p21 Waf1/Cip1 can protect human colon carcinoma cells against p53-dependent and p53-independent apoptosis induced by natural chemopreventive and therapeutic agents

“…Absence or reduced expression of the CDK inhibitor supported apoptosis under adriamycin, camptothecin, etoposide, g-irradiation, prostaglandin A2 or p53 overexpression in vitro Polyak et al, 1996;Gorospe et al, 1996Gorospe et al, , 1997 and in vivo (Waldman et al, 1997;Tian et al, 2000). Conversely, p21 overproduction through inducible expression systems or adenoviral gene transfer was protective against various insults (Wang et al, 1999b;Gorospe et al, 1996Gorospe et al, , 1997. The results presented here con®rm these ®ndings in a set of isogenic cell lines and show that the protective e ect of p21 can be functional regardless of whether apoptosis or p21-expression are regulated through p53 or other pathways (Figure 6).…”

Bcl-2 activates a programme of premature senescence in human carcinoma cells

“…In particular, activation of a senescence programme in neoplastic cells has been obtained either by reintroduction of critical regulators of replicative senescence [25,37] or by treatment with anti-cancer agents [42]. Most interestingly, expression of several CKI, in both normal and tumour cells [23,24], triggers premature senescence. Two molecular pathways appear to have a critical role in senescence in normal cells: the p16 INK4a /Rb pathway and the p53/p21 Cip1 pathway [43].…”

“…Cell lines derived from tumours are generally capable of extended proliferation: indeed, limitless replicative potential represents one of the de novo acquired capabilities of tumour cells, and the ability to repress senescence pathways appears to contribute to tumorigenesis [22]. Accordingly, restoration of senescence regulatory pathways in tumour cells rapidly elicits senescence [23][24][25]. These observations suggest that, in several immortal tumour-derived cell lines, the genetic programme of senescence is repressed, but not lost, in such a way that it can be reactivated by expression of critical regulators.…”

NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

“…Although cancer cells bypass both replicative and oncogene-induced senescence, the genetic program of senescence in these cells seems to be repressed, but not lost, in such a way that it can be reactivated by expression of critical regulators. Accordingly, restoration of senescence regulatory pathways in tumor cells rapidly elicits senescence (Wang et al, 1998(Wang et al, , 1999. In addition, a process termed stress-induced or premature senescence can be readily elicited in tumor cells by treatment with sublethal concentrations of conventional anticancer drugs (Chang et al, 1999).…”