The sirtuin 1/2 inhibitor tenovin-1 induces a nonlinear apoptosis-inducing factor-dependent cell death in a p53 null Ewing’s sarcoma cell line.

Autor: Marx, Christian, Marx-Blümel, Lisa, Lindig, Nora, Thierbach, René, Hoelzer, Doerte, Becker, Sabine, Wittig, Susan, Lehmann, Roland, Slevogt, Hortense, Heinzel, Thorsten, Wang, Zhao-Qi, Beck, James F., Sonnemann, Jürgen
Předmět:
Zdroj: Investigational New Drugs; Jun2018, Vol. 36 Issue 3, p396-406, 11p
Abstrakt: The sirtuin 1/2 inhibitor tenovin-1 activates p53 and may have potential in the management of cancer. Here, we investigated the responsiveness of Ewing’s sarcoma cells to tenovin-1. We examined its effects in two Ewing’s sarcoma cell lines with different p53 status, i.e. in p53 wild-type and p53 null cells. Effects were assessed by flow cytometric analyses of cell death, mitochondrial membrane depolarization and reactive oxygen species (ROS) generation, by caspase 3/7 activity measurement, by mRNA expression profiling and by immunoblotting. Tenovin-1 elicited caspase-mediated cell death in p53 wild-type cells, but caspase-independent cell death in p53 null cells. Remarkably, it induced a nonlinear concentration response in the latter: low concentrations of tenovin-1 were much more effective than were higher concentrations. Tenovin-1’s effects in p53 null cells involved gene expression changes of Bcl-2 family members, mitochondrial membrane depolarization, nuclear translocation of apoptosis-inducing factor, ROS formation and DNA damage; all these effects followed a bell-shaped pattern. In conclusion, our results provide new insights into tenovin-1’s mode of action by demonstrating that it can induce different pathways of cell death. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
Externí odkaz: