Mechanism of apoptosis in HL-60 cells induced by n-3 and n-6 polyunsaturated fatty acids

Kayo Arita, Hirotsugu Kobuchi, Toshihiko Utsumi, Yoshiki Takehara, Jitsuo Akiyama, Alan A. Horton, Kozo Utsumi

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

The biochemical properties and specificity of n-3 and n-6 polyunsaturated fatty acids (PUFAs) are not well known. Because PUFAs induce apoptosis of different cells, we studied the effect of various PUFAs, such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA), on the fate of cultured human promyelocytic leukemia cells (HL-60) to elucidate the mechanism of apoptosis and the difference in action between n-3 and n-6 PUFAs. Fairly low concentrations of PUFAs inhibited the growth of HL-60 cells and induced their apoptosis by a mechanism that is sensitive to DMSO, an antioxidant, and z-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk), a pan-caspase inhibitor. PUFAs stimulated the generation of reactive oxygen species (ROS) and activated various types of caspase-like proteases, such as caspase-3, -6, -8, and -9, but not caspase-1. In addition, PUFAs triggered the reaction leading to the cleavage of Bid, a death agonist member of the Bcl-2 family, and also released cytochrome c from mitochondria into the cytosol. PUFAs also decreased the mitochondrial membrane potential of intact HL-60 cells. All of these actions of n-3 PUFAs were stronger than those of AA, an n-6 PUFA, although the mechanism is not known. PUFAs stimulate swelling and membrane depolarization of isolated mitochondria in a cyclosporin A-sensitive manner. The results indicated that PUFA-induced apoptosis of HL-60 cells may be caused, in part, by direct action on the cells and by activation of the caspase cascade through cytochrome c release coupled with mitochondrial membrane depolarization.

Original languageEnglish
Pages (from-to)821-828
Number of pages8
JournalBiochemical Pharmacology
Volume62
Issue number7
DOIs
Publication statusPublished - Oct 1 2001

Fingerprint

HL-60 Cells
Unsaturated Fatty Acids
Apoptosis
Mitochondria
Depolarization
Caspases
Cytochromes c
Membranes
Arachidonic Acid
Caspase 6
Caspase 1
Caspase Inhibitors
Eicosapentaenoic Acid
Mitochondrial Membrane Potential
Omega-3 Fatty Acids
Mitochondrial Membranes
Dimethyl Sulfoxide
Caspase 3
Cytosol
Cyclosporine

Keywords

  • Apoptosis
  • Bid
  • Caspase
  • HL-60 cells
  • Membrane permeability transition
  • Polyunsaturated fatty acid

ASJC Scopus subject areas

  • Pharmacology

Cite this

Mechanism of apoptosis in HL-60 cells induced by n-3 and n-6 polyunsaturated fatty acids. / Arita, Kayo; Kobuchi, Hirotsugu; Utsumi, Toshihiko; Takehara, Yoshiki; Akiyama, Jitsuo; Horton, Alan A.; Utsumi, Kozo.

In: Biochemical Pharmacology, Vol. 62, No. 7, 01.10.2001, p. 821-828.

Research output: Contribution to journalArticle

Arita, Kayo ; Kobuchi, Hirotsugu ; Utsumi, Toshihiko ; Takehara, Yoshiki ; Akiyama, Jitsuo ; Horton, Alan A. ; Utsumi, Kozo. / Mechanism of apoptosis in HL-60 cells induced by n-3 and n-6 polyunsaturated fatty acids. In: Biochemical Pharmacology. 2001 ; Vol. 62, No. 7. pp. 821-828.
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AU - Arita, Kayo

AU - Kobuchi, Hirotsugu

AU - Utsumi, Toshihiko

AU - Takehara, Yoshiki

AU - Akiyama, Jitsuo

AU - Horton, Alan A.

AU - Utsumi, Kozo

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AB - The biochemical properties and specificity of n-3 and n-6 polyunsaturated fatty acids (PUFAs) are not well known. Because PUFAs induce apoptosis of different cells, we studied the effect of various PUFAs, such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA), on the fate of cultured human promyelocytic leukemia cells (HL-60) to elucidate the mechanism of apoptosis and the difference in action between n-3 and n-6 PUFAs. Fairly low concentrations of PUFAs inhibited the growth of HL-60 cells and induced their apoptosis by a mechanism that is sensitive to DMSO, an antioxidant, and z-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk), a pan-caspase inhibitor. PUFAs stimulated the generation of reactive oxygen species (ROS) and activated various types of caspase-like proteases, such as caspase-3, -6, -8, and -9, but not caspase-1. In addition, PUFAs triggered the reaction leading to the cleavage of Bid, a death agonist member of the Bcl-2 family, and also released cytochrome c from mitochondria into the cytosol. PUFAs also decreased the mitochondrial membrane potential of intact HL-60 cells. All of these actions of n-3 PUFAs were stronger than those of AA, an n-6 PUFA, although the mechanism is not known. PUFAs stimulate swelling and membrane depolarization of isolated mitochondria in a cyclosporin A-sensitive manner. The results indicated that PUFA-induced apoptosis of HL-60 cells may be caused, in part, by direct action on the cells and by activation of the caspase cascade through cytochrome c release coupled with mitochondrial membrane depolarization.

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