Tocopherol suppresses 24(S)-hydroxycholesterol-induced cell death via inhibition of CaMKII phosphorylation

Yuki Kimura, Minori Asa, Yasuomi Urano, Yoshiro Saito, Kiyotaka Nishikawa, Noriko Noguchi

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Although 24(S)-hydroxycholesterol (24S-OHC) plays an important role to maintain homeostasis of cholesterol in the brain, it induces neuronal cell death at high concentrations. 24S-OHC-induced cell death was suppressed by γ-tocopherol (γ-Toc) but not by γ-tocotrienol (γ-Toc3) in a similar way to α-tocopherol (α-Toc) and α-tocotrienol (α-Toc3) in human neuroblastoma SH-SY5Y cells. Both γ-Toc and γ-Toc3 significantly inhibited cumene hydroperoxide-induced cell death, as previously shown in the case of α-Toc and α-Toc3. Lipid droplet-like structure formation induced by 24S-OHC was suppressed by neither γ-Toc nor γ-Toc3. The phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) was induced by 24S-OHC, which was suppressed by CaMKII phosphorylation-site inhibitor mM3 but not by calmodulin-binding-site inhibitor KN62. A calcium chelator, BAPTA-AM, inhibited calcium ionophore A23187-induced CaMKII phosphorylation but not 24S-OHC-induced CaMKII phosphorylation. Receptor-interacting protein kinase 1 (RIPK1) phosphorylation induced by 24S-OHC was not inhibited by either mM3 or KN62, suggesting that CaMKII activation does not affect RIPK1 phosphorylation. Knockdown of RIPK1 using siRNA induced not only inhibition of CaMKII phosphorylation but also reduction of total CaMKII protein levels, suggesting that RIPK1 may regulate CaMKII signalling. 24S-OHC-induced RIPK1 phosphorylation was inhibited by neither α-Toc nor α-Toc3. In contrast, CaMKII phosphorylation induced by 24S-OHC was significantly suppressed by α-Toc but not by α-Toc3. These results suggest that CaMKII activation is involved in the mechanism of 24S-OHC-induced cell death and that Toc inhibits the cell death via inhibition of CaMKII activation through a RIPK1 phosphorylation-independent pathway.

Original languageEnglish
Pages (from-to)203-209
Number of pages7
JournalBiochimie
Volume153
DOIs
Publication statusPublished - 2018 Oct
Externally publishedYes

Keywords

  • 24(S)-hydroxycholesterol
  • CaMKII
  • Cell death
  • RIPK1
  • Tοc
  • Tοc3

ASJC Scopus subject areas

  • Biochemistry

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