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Abstract Title:

MLKL contributes to shikonin-induced glioma cell necroptosis via promotion of chromatinolysis.

Abstract Source:

Cancer Lett. 2019 12 28 ;467:58-71. Epub 2019 Sep 24. PMID: 31560934

Abstract Author(s):

Ye Ding, Chuan He, Shan Lu, Xuanzhong Wang, Chongcheng Wang, Lei Wang, Ji Zhang, Meihua Piao, Guangfan Chi, Yinan Luo, Ke Sai, Pengfei Ge

Article Affiliation:

Ye Ding

Abstract:

Chromatinolysis refers to enzymatic degradation of nuclear DNA and is regarded as one of the crucial events leading to cell death. Mixed-lineage kinase domain-like protein (MLKL) has been identified as a key executor of necroptosis, but it remains unclear whether MLKL contributes to necroptosis via regulation of chromatinolysis. In this study, we find that shikonin induces MLKL activation and chromatinolysis in glioma cells in vitro and in vivo, which are accompanied with nuclear translocation of AIF andγ-H2AX formation. In vitro studies reveal that inhibition of MLKL with its specific inhibitor NSA or knockdown of MLKL with siRNA abrogates shikonin-induced glioma cell necroptosis, as well as chromatinolysis. Mechanistically, activated MLKL targets mitochondria and triggers excessive generation ofmitochondrial superoxide, which promotes AIF translocation into nucleus via causing mitochondrial depolarization and aggravates γ-H2AX formation via improving intracellular accumulation of ROS. Inhibition of nuclear level of AIF by knockdown of AIF with siRNA or mitigation of γ-H2AX formation bysuppressing ROS with antioxidant NAC effectively prevents shikonin-induced chromatinolysis. Then, we found that RIP3 accounts for shikonin-induced activation of MLKL, and activated MLKL reversely up-regulates the protein level of CYLD and promotes the activation of RIP1 and RIP3. Taken together, ourdata suggest that MLKL contributes to shikonin-induced glioma cell necroptosis via promotion of chromatinolysis, and shikonin induces a positive feedback between MLKL and its upstream signals RIP1 and RIP3.

Study Type : In Vitro Study
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Pharmacological Actions : Cytotoxic : CK(76) : AC(60)

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