Senovilla Laura, Vitale Ilio, Galluzzi Lorenzo, Vivet Sonia, Joza Nicholas, Younes Amena Ben, Rello-Varona Santiago, Castedo Maria, Kroemer Guido
INSERM, U848, and Institut Gustave Roussy, and Université Paris Sud-XI, 11, Villejuif, France.
Cell Cycle. 2009 May 1;8(9):1380-5. doi: 10.4161/cc.8.9.8305. Epub 2009 May 26.
Tetraploidy may constitute a metastable state leading to numeric and structural chromosome abnormalities that are associated with cancer. Here, we show that cultured primary p53(-/-) (but not wild type, WT) mouse mammary epithelial cells (MMECs) accumulate a tetraploid sub-population in vitro. This occurs spontaneously, yet can be exacerbated by the addition of microtubule inhibitors as well as of inhibitors of cytokinesis. As compared to WT cells, tetraploid p53(-/-) MMECs contain supernumerary centrosomes and exhibit a reduced propensity to initiate the mitochondrial pathway of apoptosis. Moreover, tetraploid p53(-/-) MMECs are more resistant against anthracyclin-induced cell killing than their diploid counterparts. Altogether, these data indicate that p53 normally suppresses the generation of tetraploid cells, presumably by activating the intrinsic pathway of apoptosis. In the absence of p53, tetraploid cells accumulate as a result of inhibited apoptosis, which contributes to the acquisition of chemotherapy resistance.
四倍体可能构成一种亚稳态，导致与癌症相关的染色体数目和结构异常。在此，我们表明，培养的原代p53基因敲除（而非野生型，WT）小鼠乳腺上皮细胞（MMECs）在体外会积累一个四倍体亚群。这是自发发生的，但添加微管抑制剂以及胞质分裂抑制剂会加剧这种情况。与WT细胞相比，四倍体p53基因敲除的MMECs含有多余的中心体，并且启动线粒体凋亡途径的倾向降低。此外，四倍体p53基因敲除的MMECs比其二倍体对应物对蒽环类药物诱导的细胞杀伤更具抗性。总之，这些数据表明p53通常通过激活内在凋亡途径来抑制四倍体细胞的产生。在缺乏p53的情况下，四倍体细胞由于凋亡受到抑制而积累，这有助于获得化疗抗性。
