Activation of the p53 pathway induces a-smooth muscle actin expression in both myeloid leukemic cells and normal macrophages

作者：Secchiero Paola^*; Rimondi Erika; Di Iasio Maria Grazia; Voltan Rebecca; Gonelli Arianna; Zauli Giorgio

来源：Journal of Cellular Physiology, 2012, 227(5): 1829-1837.

DOI：10.1002/jcp.22910

A range of cell types of mesenchymal origin express a-smooth muscle actin (a-SMA), a protein that plays a key role in controlling cell motility and differentiation along the fibrocyte and myofibroblast lineages. Although a-SMA is often expressed in stromal cells associated to a variety of cancers including hematological malignancies, up to now the role of anti-cancer drugs on a-SMA has not been deeply investigated. In this study, we demonstrated that Nutlin-3, the small molecule inhibitor of the MDM2/p53 interactions, significantly up-regulated the mRNA and protein levels of a-SMA in normal macrophages as well as in p53wild-type but not in p53mutated/null myeloid leukemic cells. The p53-dependence of a-SMA up-regulation induced by Nutlin-3 was demonstrated in experiments performed with siRNA for p53. Of note, Nutlin-3 mediated up-regulation of a-SMA in OCI leukemic cells was accompanied by cell adhesion to plastic substrate and by reduced cell migratory response in transwell assays. Notably, the role of a-SMA induction in the modulation of myeloid cell migration was clearly documented in a-SMA gene knockdown experiments. In addition, Nutlin-3 significantly up-regulated a-SMA expression in primary endothelial cells, but not in fibroblasts and mesenchymal stem cells (MSC). Conversely, transforming growth factor-beta 1 up-regulated a-SMA in fibroblasts and MSC, but not in macrophages and endothelial cells. Taken together, these data indicate that Nutlin-3 is a potent inducer of a-SMA in both normal and leukemic myeloid cells as well as in endothelial cells. J. Cell. Physiol. 227: 18291837, 2012.

• 出版日期2012-5