Protective role of cisplatin in ischemic liver injury through induction of autophagy.
High mobility group box 1 (HMGB1) is a nuclear protein released from stressed or damaged cells that activates inflammatory cascades involved in the pathogenesis of liver ischemia reperfusion (I/R) injury. In efforts to develop strategies aimed at preventing its release from ischemic cells following I/R, we studied the use of cisplatin, a member of the platinating chemotherapeutic agents capable of inducing DNA lesions that have high binding affinities for high mobility group proteins inside the nucleus of cells. In addition to demonstrating that cisplatin prevents liver damage associated with liver I/R by sequestering HMGB1 inside the nucleus of ischemic cells, cisplatin also alters cell survival signaling through autophagy. Our results provide a potential approach involving the use of platinating agents and their effects on autophagy in mitigating the deleterious effects of ischemia reperfusion-mediated disease processes.
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Jon
J
Cardinal
Pinhua
P
Pan
Allan
A
Tsung
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000378:metabolism; D007511:Ischemia / Q000150:complications* / Q000473:pathology; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D008107:Liver Diseases / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D024243:HMGB1 Protein; D020011:Protective Agents; D017382:Reactive Oxygen Species; D002945:Cisplatin