Abstract
p53 gene therapy can induce tumor regression, but the low efficacy of in vivo gene transfer has greatly hampered the mechanistic analysis of this antitumoral activity. We therefore used a p53-null human NSCLC cell line in which we reintroduced the wild-type p53 gene under control of a tetracycline-dependent promoter. P53 induction provokes cell cycle arrest in G0/G1 and G2/M phase, an up-regulation of p21, a down-regulation of cyclin B1 and appearance of senescence features without down-regulation of human telomerase reverse transcriptase. No detectable morphological changes of apoptosis nor procaspase-3 activation are observed. In subcutaneous tumors grafted in nude mice, the induction of p53 expression leads to a complete and long-lasting tumor regression in 28 days which is associated with cell cycle arrest, but not detectable apoptosis nor inhibition of angiogenesis. These results show that irreversible cell cycle arrest is sufficient to elicit tumor regression after p53 gene transfer in p53-deficient tumor cells.
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Acknowledgements
The authors thank Dominique Desplanques et Corine Tenaud for technical assistance. This work was supported by ARC (Association de Recherche Contre le Cancer), the Ligue Nationale de Lutte Contre le Cancer (Unité de l'Isère) and FEGEFUC, as well as by grants from the region Rhône-Alpes (programme emergence) and from the Health Ministry (CRTG). Laurence Dubrez acknowledges ARC and region Rhône-Alpes for research fellowships.
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Dubrez, L., Coll, JL., Hurbin, A. et al. Cell cycle arrest is sufficient for p53-mediated tumor regression. Gene Ther 8, 1705–1712 (2001). https://doi.org/10.1038/sj.gt.3301592
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DOI: https://doi.org/10.1038/sj.gt.3301592
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