Doxorubicin-induced necrosis is mediated by poly-(ADP-ribose) polymerase 1 (PARP1) but is independent of p53

Abstract

Necrosis, unregulated cell death, is characterized by plasma membrane rupture as well as nuclear and cellular swelling. However, it has recently been reported that necrosis is a regulated form of cell death mediated by poly-(ADP-ribose) polymerase 1 (PARP1). PARP1 is thought to mediate necrosis by inducing DNA damage, although this remains unconfirmed. In this study, we examined the mechanisms of PARP1-mediated necrosis following doxorubicin (DOX)-induced DNA damage in human kidney proximal tubular (HK-2) cells. DOX initiated DNA damage response (DDR) and upregulated PARP1 and p53 expression, resulting in morphological changes similar to those observed during necrosis. Additionally, DOX induced mitochondrial hyper-activation, as evidenced by increased mitochondrial respiration and cytosolic ATP (cATP) production. However, DOX affected mitochondrial mass. DOX-induced DNA damage, cytosolic reactive oxygen species (cROS) generation, and mitochondrial hyper-activation decreased in cells with inhibited PARP1 expression, while generation of nitric oxide (NO) and mitochondrial ROS (mROS) remained unaffected. Moreover, DOX-induced DNA damage, cell cycle changes, and oxidative stress were not affected by p53 inhibition. These findings suggest that DNA damage induced necrosis through a PARP1-dependent and p53-independent pathway.

Antiproliferative and toxicogenomic effects of resveratrol in bladder cancer cells with different TP53 status

“…Shin et al (2015) demonstrated that doxorubicin treatment induces DNA breaks and increases PARP levels, even with a p53 inhibitor. In T24 cells, there was an increase in necrosis rates after treatment with resveratrol.…”

“…This death pathway may occur independently of p53. Shin et al (2015) demonstrated that doxorubicin treatment induces DNA breaks and increases PARP levels, even with a p53 inhibitor. High PARP levels result in exacerbated activation of the mitochondria leading to necrosis.…”

An Overview of Pathways of Regulated Necrosis in Acute Kidney Injury

“…93 This again indicated that the availability of ATP might be an important factor for the decision between energy-consuming apoptosis and necrosis. Inhibition of PARP-1 up-regulation was shown to prevent RN in various toxic settings in vitro in cultured tubular epithelial cells 95,96 and in vivo. [97][98][99] During renal IRI, PAR increased in nuclei from tubular epithelial cells, indicating poly(ADP-ribosyl)ation (PARylation) of nuclear proteins to initiate the DNA damage repair mechanism.…”

DNA damage response in nephrotoxic and ischemic kidney injury

“…In addition to apoptosis, DNA damage may also induce other forms of cell death, although classical DDR may not be involved. For example, DNA damage induces the activation of poly-(ADP-ribose) polymerase 1 (PARP1), which may trigger necrosis (Shin et al, 2015). …”