Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs

Abstract

Exposure of human tumor cell lines to moderate doses of anticancer agents induces terminal proliferation arrest accompanied by morphologic and enzymatic changes that resemble senescence of normal cells. We have investigated the role of p53 and p21 waf1/cip1 in the induction of this response in drug-treated tumor cells. Doxorubicin treatment induced the senescence-like phenotype (SLP) and its associated terminal growth arrest in wild-type HCT116 colon carcinoma cells; this response was strongly decreased but not abolished in HCT116 lines with homozygous knockout of p53 or p21. Transduction of HT1080 ®brosarcoma cells with a genetic inhibitor of p53 also decreased the induction of SLP and increased drug-induced mitotic cell death. To determine if drugstimulated p21 expression was responsible for senescence-like growth arrest, we have expressed dierent levels of p21 from an inducible promoter. While highlevel overexpression of p21 was sucient to induce SLP in HT1080 cells, the levels of p21 expressed in doxorubicin-treated cells could account for only a fraction of doxorubicin-induced SLP. Our results indicate that p53 and p21 act as positive regulators of senescence-like terminal proliferation arrest, but their function is neither sucient nor absolutely required for this treatment response in tumor cells.

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Analyses of cells harboring faults in p21 and p53 within different cellular models of anticancer treatment suggest varied outcomes that depend on the initiating response pathway. In response to cytotoxic drugs, tumor cells may display characteristics of senescence or autophagy by delaying apoptosis at early time points of cytotoxic stress or, at higher toxic doses, tumor cells may display characteristics of apoptosis and, at later time points, of repressed senescence (Chang et al, 1999). Moreover, each type of cellular response results in a very different clonogenic potential.…”

A nuclear budding mechanism in transiently arrested cells generates drug-sensitive and drug-resistant cells

“…Senescence is defined as a cell program of terminal growth arrest that can be activated after chemotherapy [10]. Senescence is considered largely p53-dependent, while the onset of mitotic catastrophe is not [11,12]. Several DNA-binding drugs have been reported to produce mitotic catastrophe in both cells containing wild-type p53 and those bearing mutated or deleted p53 genes [13][14][15][16][17].…”

“…Senescence may also follow mitotic catastrophe if polyploid cells are arrested in G1 or G2 after mitotic catastrophe [13,24], but the arrest is not permanent when, for example, cells lack p53 function, or the p53 and p21 WAF1 protein levels decrease after treatment with certain drugs [7,11,13,21,22,25], or as a result of alterations in the phosphorilation of Chk1 [19]. Therefore, cells can re-enter the cell cycle, increasing their polyploidy before they eventually die.…”

p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells

“…Nevertheless, p21 mutations in human cancer are rare (Hall and Peters, 1996), and p21 knockout mice develop normally and do not show an increased rate of tumorigenesis (Deng et al, 1995). Increased p21 expression leads to cell growth arrest (Noda et al, 1994), which occurs in both G1 and G2 (Niculescu et al, 1998) and is accompanied by the development of morphologic and phenotypic markers of senescence in some or all cells (Vogt et al, 1998;McConnell et al, 1998;Bates et al, 1998;Fang et al, 1999;Chang et al, 1999a). p21-mediated growth arrest stems from its ability to inhibit cyclin-dependent kinase (CDK) complexes that regulate transitions between di erent phases of the cell cycle (Gartel and Tyner, 1998).…”