Suppression of apoptosis by bcl-2 does not prevent p53-mediated control of experimental metastasis and anchorage dependence

Abstract

Mutations in the p53 tumor suppressor gene are frequently associated with the metastatic stage of tumor progression. Inactivation of p53 was shown to promote metastasis under experimental conditions. To determine the p53 functions that are involved in the control of tumor metastasis, we compared properties of three types of transformed mouse ®broblasts: with intact p53, with p53-mediated apoptosis suppressed by bcl-2 and with p53 inactivated by dominant negative mutants. Although expression of bcl-2 blocked apoptosis in detached cells and increased tumor cell survival in the blood circulation, it was insu cient to a ect the ability of p53 to cause cell cycle arrest in detached cells and suppress experimental metastasis. For the suppression of metastasis complete inactivation of p53 was required. We conclude that the apoptotic function of p53 is dispensable for the p53-dependent suppression of experimental metastasis that is presumably achieved by controlling anchorage dependence. These data provide a possible explanation to dramatic di erences in values of bcl-2 and mutant p53 as prognostic markers in human cancer.

Apoptosis induced by denied adhesion to extracellular matrix (anoikis) in thyroid epithelial cells is p53 dependent but fails to correlate with modulation of p53 expression

“…Our study indicates that, like in transformed ¢broblasts, in epithelial thyroid cells an excess of wild-type-like p53 induced apoptosis whereas inactivation of endogenous p53 inhibited anoikis. However, in contrast to transformed ¢broblasts [4], modulation of p53 expression was not observed at any time during anoikis, indicating that to accomplish its apoptotic pathway, denied adhesion does not require variations of expression of p53 itself nor of p53-modulated apoptotic factors. This di¡erence between ¢broblasts and epithelial cells may be attributed to the di¡erent response to the microenvironment of these two cell types, since transformation sensitizes ¢bro-blasts to anoikis whereas it renders epithelial cells resistant [5].…”

Identification of RASSF8 as a candidate lung tumor suppressor gene

“…Clonogenic assay of RASSF8-transfected and control A549 cells revealed no significant effect of RASSF8 protein overexpression on cancer cell viability, since colony numbers were similar. However, anchorage-independent growth in soft agar, which is correlated with tumor progression and metastasis formation (Nikiforov et al, 1996;Clezardin, 1998;Jiang et al, 2001;Malaney and Daly, 2001;Nakanishi et al, 2002), was significantly reduced in the RASSF8-transfected A549 cells (Figure 3b and c). Moreover, RASSF8 transfection inhibited clonogenic activity in NCI-H520 cancer cell line.…”

Apoptosis Inhibitor as a Suppressor of Tumor Progression: Expression of Bcl-2 Eliminates Selective Advantages for p53-Deficient Cells in the Tumor

“…C8 cells maintain wild type p53 status, making them a conventional model for p53-dependent apoptosis for in vitro and in vivo studies. 4,16,17 Inactivation of p53 function in these cells was achieved by transduction with retrovirus expressing the C-terminal portion of p53 (GSE56, see ref. 16), acting as dominant negative mutant.…”

“…Both genetic alterations are frequently acquired during tumor progression conferring resistance to hypoxia 2,3 and increasing cell survival in circulation in the experimental animal model. 4 Review of clinical data indicates that p53 deficiency and Bcl-2 expression are rarely combined in one tumor and usually appear as alternative traits, [5][6][7][8][9][10] suggesting that they could be the alternative ways to reach the same type of selective advantage. However, there are reports indicating that these two genetic alterations have opposite prognostic values in some types of cancer: while the inactivation of p53 is associated with rapid progression and considered a negative prognostic factor, [5][6][7]9 the expression of Bcl-2 was often found to be associated with favorable prognosis in breast, ovarian and some other solid cancers.…”