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Promyelocytic leukemia protein-induced growth suppression and cell death in liver cancer cells

Abstract

The promyelocytic leukemia protein (PML), involved in the pathogenesis of acute promyelocytic leukemia, is a coactivator of p53 tumor suppressive functions. The ability of PML to inhibit growth and induce cell death in solid tumor cells, however, has not been determined. We therefore assayed the tumor suppressor activities of PML and compared them with those of p53 in four liver cancer cell lines. Following infection of cells with replication-deficient recombinant PML adenovirus, the exogenous PML localized in the nucleus and formed abnormally enlarged PML–nuclear bodies after 24 hours. In vitro growth curve analysis showed that the overexpressed PML initially induced a substantial G1 cell cycle arrest and triggered massive cell death in all tested cell lines, irrespective of their p53 status. PML-induced cell death decreased by about 30% in the presence of a broad caspase inhibitor, zVAD. The cell death effect of PML was higher than that induced by p53 over a longer period of time. As with p53, overexpression of PML was closely related to upregulation of p21 and decrease of cyclin D1 expression. Unexpectedly, retinoic acid (RA) antagonized rather than enhanced PML-triggered cell death. RA enhanced the expression of adenovirus–cytomegalovirus-promoted PML at both transcription and protein levels within 12 hours after treatment; however, the PML protein was significantly degraded in the presence of RA at days 3–5 postinfection. PML degradation was also observed in SK-BR3 breast cancer cells treated with RA. Taken together, our findings strongly support the hypothesis that PML acts as a strong independent cell death inducer and that RA conversely abolishes the therapeutic effects of the PML proteins through proteasomal degradation of the protein.

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Acknowledgements

This study was supported by Grants (2003-309 and 2004-309) from the Asan Institute for Life Science, Seoul, Korea.

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Correspondence to Jene Choi.

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Son, SH., Yu, E., Choi, E. et al. Promyelocytic leukemia protein-induced growth suppression and cell death in liver cancer cells. Cancer Gene Ther 12, 1–11 (2005). https://doi.org/10.1038/sj.cgt.7700755

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