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Acta Pharmacol Sin. 2017 Nov;38(11):1543-1553. doi: 10.1038/aps.2017.112. Epub 2017 Aug 17.

Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation.

Lu B1,2, Gong X3, Wang ZQ1,2, Ding Y1,2, Wang C1,2, Luo TF2,4, Piao MH5, Meng FK6, Chi GF7, Luo YN1, Ge PF1,2.

Author information

  • 1Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
  • 2Research Center of Neuroscience, First Hospital of Jilin University, Changchun 130021, China.
  • 3Department of Hand Surgery, First Hospital of Jilin University, Changchun 130021, China.
  • 4Department of Neurology, First Hospital of Jilin University, Changchun 130021, China.
  • 5Department of Anesthesiology, First Hospital of Jilin University, Changchun 130021, China.
  • 6Department of Neurosurgery, People's Hospital of Jilin Province, Changchun 130021, China.
  • 7Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.

Abstract

Necroptosis is a type of programmed necrosis regulated by receptor interacting protein kinase 1 (RIP1) and RIP3. Necroptosis is found to be accompanied by an overproduction of reactive oxygen species (ROS), but the role of ROS in regulation of necroptosis remains elusive. In this study, we investigated how shikonin, a necroptosis inducer for cancer cells, regulated the signaling leading to necroptosis in glinoma cells in vitro. Treatment with shikonin (2-10 μmol/L) dose-dependently triggered necrosis and induced overproduction of intracellular ROS in rat C6 and human SHG-44, U87 and U251 glioma cell lines. Moreover, shikonin treatment dose-dependently upregulated the levels of RIP1 and RIP3 and reinforced their interaction in the glioma cells. Pretreatment with the specific RIP1 inhibitor Nec-1 (100 μmol/L) or the specific RIP3 inhibitor GSK-872 (5 μmol/L) not only prevented shikonin-induced glioma cell necrosis but also significantly mitigated the levels of intracellular ROS and mitochondrial superoxide. Mitigation of ROS with MnTBAP (40 μmol/L), which was a cleaner of mitochondrial superoxide, attenuated shikonin-induced glioma cell necrosis, whereas increasing ROS levels with rotenone, which improved the mitochondrial generation of superoxide, significantly augmented shikonin-caused glioma cell necrosis. Furthermore, pretreatment with MnTBAP prevented the shikonin-induced upregulation of RIP1 and RIP3 expression and their interaction while pretreatment with rotenone reinforced these effects. These findings suggest that ROS is not only an executioner of shikonin-induced glioma cell necrosis but also a regulator of RIP1 and RIP3 expression and necrosome assembly.

PMID:
28816233
PMCID:
PMC5672068
[Available on 2018-11-01]
DOI:
10.1038/aps.2017.112
[PubMed - in process]
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