Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells

• Toyomura Kaori

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

• Saito Takeshi

  Laboratory of Environmental Health Sciences, Faculty of Health Sciences, Hokkaido University

• Emori Syunsuke

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

• Matsumoto Ikiru

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

• Kato Erina

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

• Kaneko Masayuki

  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science

• Okuma Yasunobu

  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science

• Nakamura Hiroyuki

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

• Murayama Toshihiko

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

抄録

The inhibitors of heat shock protein-90 (Hsp90), geldanamycin (GA) and 17-(allylamino)-17-desmethoxygeldanamycin, show various cellular effects including destabilization of Hsp90 clients and expression of other chaperones, etc. and modulate cytotoxicity depending on cell types and stimuli. In this study, we investigated the effects of Hsp90 inhibitors on survival of PC12 cells with and without cytotoxic stimuli including orthovanadate, Na₃VO₄. Treatment with Hsp90 inhibitors at 2 µM for 16 hr did not cause cell detachment and leakage of lactate dehydrogenase, and at concentrations greater than 5 µM resulted in cytotoxicity. The inhibitors at 2 µM enhanced the cytotoxicity of 1 mM Na₃VO₄, and did not protect PC12 cells at any concentrations against Na₃VO₄. Next, the effects of Hsp90 inhibitors on the intracellular metabolism of ceramide and arachidonic acid (AA) were examined, since these processes also regulate cytotoxicity. In cells treated with 4-nitrobenzo-2-oxa-1,3-diazole (NBD)-labeled C6-ceramide, Hsp90 inhibitors reduced the formation of NBD-glucosylceramide and Na₃VO₄-induced formation of NBD-caproic acid, a counterpart of sphingosine, without affecting other metabolites including NBD-sphingomyelin. GA treatment did not change the amounts of AA released in PC12 cells with and without Na₃VO₄. In HeLa cells, however, GA treatment decreased the release of AA via cytosolic phospholipase A₂α’s activation probably because of dysfunctional Hsp90 clients. Our results suggest the possible involvement of ceramide metabolism, not AA release, in GA-induced cytotoxicity in PC12 cells.

収録刊行物

• Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｔｏｘｉｃｏｌｏｇｉｃａｌ　Ｓｃｉｅｎｃｅｓ

  Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｔｏｘｉｃｏｌｏｇｉｃａｌ　Ｓｃｉｅｎｃｅｓ 37 (5), 1049-1057, 2012

  一般社団法人　日本毒性学会

キーワード

• Hsp90
• Geldanamycin
• Cytotoxicity
• Ceramide
• Arachidonic acid
• PC12 cells

詳細情報

• CRID: 1390001204905700864
• NII論文ID: 130004446994
• NII論文ID: 10030876757
• NII書誌ID: AN00002808
• DOI: 10.2131/jts.37.1049
• COI: 1:STN:280:DC%2BC3s%2Fis1OmsA%3D%3D
• ISSN: 18803989
• ISSN: 03881350
• NDL書誌ID: 024030416
• PubMed: 23038012
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I024030416
• Web Site: https://www.jstage.jst.go.jp/article/jts/37/5/37_1049/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2013338502
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
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