Quercetin enhancement of arsenic-induced apoptosis via stimulating ROS-dependent p53 protein ubiquitination in human HaCaT keratinocytes

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23 Citations (Scopus)

Abstract

In this study, QUE, but not the structurally related chemical, rutin, enhanced the cytotoxicity of arsenic trioxide (As+3) against the viability of normal human HaCaT keratinocytes via induction of apoptosis. QUE enhancement of As+3-mediated apoptosis was accompanied by increased intracellular peroxide production according to a DCFH-DA analysis, and DNA ladders induced by QUE/As+3 were inhibited by adding the antioxidative compound, N-acetyl cysteine (NAC). A loss of the mitochondrial membrane potential by QUE/As+3 was observed according to DiOC6 staining in concert with increased Bax protein and cytosolic cytochrome (Cyt) c protein expression in HaCaT cells, which was prevented by the addition of NAC. A decrease in the p53 protein with increased protein ubiquitination was detected in QUE/As+3-treated HaCaT cells, and this was prevented by the addition of NAC. The decrease in the p53 protein by QUE/As+3 was reversed by adding the proteasome inhibitor, MG132. L-Buthionine sulphoximine (BSO) enhanced the cytotoxicity of As+3 against the viability of HaCaT cells with reduced p53 protein through inducing protein ubiquitination and reactive oxygen species (ROS) production, and disrupting the mitochondrial membrane potential in HaCaT cells. Additionally, QUE and BSO enhanced the cytotoxic effects of monomethylarsonous acid (MMA+3) but not other arsenic compounds in accordance with increased p53 protein ubiquitination in HaCaT cells. QUE plus As+3 stimulation of apoptosis in human HaCaT keratinocytes via activating ROS-dependent p53 protein ubiquitination may offer a rationale for the use of QUE to improve the clinical efficacy of arsenics in treating psoriasis.

Original languageEnglish
Pages (from-to)370-375
Number of pages6
JournalExperimental Dermatology
Volume21
Issue number5
DOIs
Publication statusPublished - May 2012

Keywords

  • Arsenics-reactive oxygen species
  • Keratinocytes-ubiquitination
  • Quercetin

ASJC Scopus subject areas

  • Dermatology
  • Molecular Biology
  • Biochemistry

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