PARP-1 Inhibition Increases Oxidative Stress in Ets-1-Expressing MDA-MB-231 Breast Cancer Cells

Abstract

Background

The Ets-1 transcription factor plays a primordial role in regulating the expression of numerous genes implicated in cancer progression. In a previous study, we revealed that poly(ADP-ribose) polymerase-1 (PARP-1) inhibition by PJ-34 results in Ets-1 level increase in cells, which is related with cell death of Ets-1-expressing cancer cells.

Aims

The mechanism of the antitumor effect of PARP-1 inhibition was investigated in the Ets-1-expressing MDA-MB-231 breast cancer cells.

Methods and Results

We tested the effects of four PARP inhibitors (PARPi) (PJ-34, Veliparib, Olaparib, and Rucaparib). We first demonstrated that PARPi reduced cells growth through G2/M cell cycle arrest. Next, we evaluated PARP-1 inhibition effect on oxidative DNA damage in Ets-1-overexpressing and Ets-1-non-expressing breast cancer cells and we showed that PARPi led only Ets-1-overexpressing cells to accumulate it, which triggers the DNA damage response as revealed by the increase in the level of a panel of DNA damage-related proteins. Importantly, we demonstrated that PARPi increased reactive oxygen species (ROS), only in Ets-1-overexpressing cells and this is accompanied by upregulation of p47^phox expression, a subunit of the NAPDH oxidase (NOX).

Conclusion

These preliminary findings correlate PARPi-induced oxidative DNA damage/oxidative stress to Ets-1 expression in breast cancer cells.