title: Etoposide Induces Necrosis Through p53-Mediated Antiapoptosis in Human Kidney Proximal Tubule Cells.
abstract: The p53 protein is an important transcription factor that modulates signaling pathways for both cell death and survival. Its antiapoptotic mechanisms that correlate with necrotic and apoptotic cell death are not well understood. Here, we report that etoposide promotes progression of the DNA damage response as well as necrotic morphological changes including plasma membrane rupture using carbon nanotube-tipped/atomic force microscopy (CNT/AFM) probes in human kidney proximal tubule (HK-2) cells. Inhibition of p53 abrogated cell cycle arrest and led to a decrease in the expression levels of repair proteins that were induced by DNA damage. Mitochondrial biogenesis and cytosolic production of reactive oxygen species were also reduced after p53 inhibition; the latter change induced mitochondrial superoxide accumulation and mitochondrial damage, which triggered the activation of caspase 3. Inhibition of p53 also led to a loss of cell adhesion and converted necrotic cell death to apoptotic cell death, with appreciable cell shrinkage and appearance of apoptotic bodies that were observed using CNT/AFM probes. Thus, our study demonstrated that p53 protects against apoptosis, and leads to etoposide-induced necrosis. These results are expected to aid in the understanding of mechanism of antiapoptosis and its relationship to cell death.
authors.affiliation: *Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea and.
authors.forename: Hyuk-Kwon
authors.initials: HK
authors.lastname: Kwon
authors.affiliation: *Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea and.
authors.forename: Hyeon-Jun
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: *Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea and.
authors.forename: Jae-Hyeok
authors.initials: JH
authors.lastname: Lee
authors.affiliation: *Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea and.
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Park
authors.affiliation: *Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea and.
authors.forename: Min-Cheol
authors.initials: MC
authors.lastname: Kwon
authors.affiliation: *Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea and.
authors.forename: Suresh
authors.initials: S
authors.lastname: Panneerselvam
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Chan Gyu
authors.initials: CG
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
authors.affiliation: *Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea and jhkim@ajou.ac.kr.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: *Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea and sangdunchoi@ajou.ac.kr.
authors.forename: Sangdun
authors.initials: S
authors.lastname: Choi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000009:adverse effects / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009336:Necrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D001678:Organelle Biogenesis; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D045643:DNA Repair Enzymes
keywords: antiapoptosis; apoptosis; etoposide; necrosis; p53