title: 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.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea.
authors.forename: Hyeon-Jun
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea.
authors.forename: Hyuk-Kwon
authors.initials: HK
authors.lastname: Kwon
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea.
authors.forename: Jae-Hyeok
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea.
authors.forename: Xiangai
authors.initials: X
authors.lastname: Gui
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea.
authors.forename: Asma
authors.initials: A
authors.lastname: Achek
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea.
authors.forename: Sangdun
authors.initials: S
authors.lastname: Choi
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D004317:Doxorubicin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases