Nutlin-3a induces cytoskeletal rearrangement and inhibits the migration and invasion capacity of p53 wild-type cancer cells.
MDM2 is an E3 ubiquitin ligase that binds and ubiquitinates the tumor suppressor protein p53, leading to its proteasomal degradation. Nutlin-3a (Nutlin) is a preclinical drug that binds MDM2 and prevents the interaction between MDM2 and p53, leading to p53 stabilization and activation of p53 signaling events. Previous studies have reported that Nutlin promotes growth arrest and/or apoptosis in cancer cells that express wild-type p53. In the current study, Nutlin treatment caused a cytoskeletal rearrangement in p53 wild-type human cancer cells from multiple etiologies. Specifically, Nutlin decreased actin stress fibers and reduced the size and number of focal adhesions in treated cells. This process was dependent on p53 expression but was independent of p21 expression and growth arrest. Consistent with this, Nutlin-treated cells failed to form filamentous actin-based motility structures (lamellipodia) and displayed significantly decreased directional persistence in response to migratory cues. Finally, chemotactic assays showed a p53-dependent/p21-independent decrease in migratory and invasive capacity of Nutlin-treated cells. Taken together, these findings reveal that Nutlin treatment can inhibit the migration and invasion capacity of p53 wild-type cells, adding to the potential therapeutic benefit of Nutlin and other small molecule MDM2 inhibitors. Mol Cancer Ther; 9(4); 895-905. (c)2010 AACR.
Moran
Diarmuid M
DM
Rush University Medical Center, Department of Anatomy and Cell Biology, 1653 West Congress Parkway, Jelke 1306, Chicago, IL 60612, USA.
Maki
Carl G
CG
D000199:Actins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism*; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D010879:Piperazines / Q000494:pharmacology*; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000199:Actins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3