Apoptosis-mediated cytotoxicity of prodigiosin-like red pigment produced by γ-Proteobacterium and its multiple bioactivities

Takuji Nakashima*, Tadashi Tamura, Maki Kurachi, Kenichi Yamaguchi, Tatsuya Oda

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Recently we discovered a bacterial strain (MS-02-063) that produces large amounts of red pigment (PG-L-1). Among the cell lines tested, U937 cells showed the highest susceptibility to PG-L-1 toxicity. PG-L-1 induced typical apoptotic nuclear morphological changes, and single cell gel electrophoresis revealed that PG-L-1 caused DNA fragmentation in U937 cells. In PG-L-1 treated U937 cells, the acidic compartment such as lysosomes disappeared, suggesting that PG-L-1-induced disorder of intracellular pH compartmentalization might trigger apoptotic signal. Since p38 MAP kinase inhibitor specifically prevented the PG-L-1 mediated cell death, p38 MAP kinase may be involved in the cytotoxic mechanism. In fact, immunoblot analysis of p38 MAP kinase revealed that phosphorylation of p38 MAP kinase occurred in PG-L-1-treated U937 cells. In addition to the activity to induce apoptotic cell death as reported in several PG family members, our chemiluminescence analysis suggested that PG-L-1 inhibited superoxide generation by 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated U937 cells in a dose-dependent manner. Since PG-L-1 had no effect on the chemiluminescence response caused by xanthine oxidase/hypoxanthine system, PG-L-1 acts on the enzyme system responsible for O2 - generation rather than direct scavenging toward O2 -. Our results suggest that PG-L-1 causes multiple biochemical effects on the target cells such as increase in pH in acidic intracellular compartment, activation of p38 MAP kinase, inhibition of O2 - generation, and eventually induces apoptotic cell death.

Original languageEnglish
Pages (from-to)2289-2295
Number of pages7
JournalBiological and Pharmaceutical Bulletin
Volume28
Issue number12
DOIs
Publication statusPublished - 2005 Dec
Externally publishedYes

Keywords

  • Apoptosis
  • Prodigiosin
  • Superoxide
  • U937 cell
  • γ-proteobacterium

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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