Mitochondrial signal lacking manganese superoxide dismutase failed to prevent cell death by reoxygenation following hypoxia in a human pancreatic cancer cell line, KP4.

Abstract

One of the major characteristics of tumor is the presence of a hypoxic cell population, which is caused by abnormal distribution of blood vessels. Manganese superoxide dismutase (MnSOD) is a nuclear-encoded mitochondrial enzyme, which scavenges superoxide generated from the electron-transport chain in mitochondria. We examined whether MnSOD protects against hypoxia/reoxygenation (H/R)-induced oxidative stress using a human pancreas carcinoma-originated cell line, KP4. We also examined whether MnSOD is necessarily present in mitochondria to have a function. Normal human MnSOD and MnSOD without a mitochondrial targeting signal were transfected to KP4 cells, and reactive oxygen species, nitric oxide, lipid peroxidation, and apoptosis were examined as a function of time in air following 1 day of hypoxia as a H/R model. Our results showed H/R caused no increase in nitric oxide, but resulted in increases in reactive oxygen species, 4-hydroxy-2-nonenal protein adducts, and apoptosis. Authentic MnSOD protected against these processes and cell death, but MnSOD lacking a mitochondrial targeting signal could not. These results suggest that only when MnSOD is located in mitochondria is it efficient in protecting against cellular injuries by H/R, and they also indicate that mitochondria are primary sites of H/R-induced cellular oxidative injuries.

• Authors: Futoshi Hirai, Shigeatsu Motoori, Shizuko Kakinuma, Kazuo Tomita, Hiroko P Indo, Hirotoshi Kato, Taketo Yamaguchi, Hsiu-Chuan Yen, Daret K St Clair, Tetsuo Nagano, Toshihiko Ozawa, Hiromitsu Saisho, Hideyuki J Majima
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 6 Issue 3 Pg. 523-35 (Jun 2004) ISSN: 1523-0864 [Print] United States
• PMID: 15130279 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aldehydes
• DNA Adducts
• DNA Primers
• DNA, Complementary
• RNA, Messenger
• Reactive Oxygen Species
• Nitric Oxide
• Superoxide Dismutase
• 4-hydroxy-2-nonenal
• Oxygen

Topics

• Aldehydes (chemistry)
• Apoptosis
• Cell Death
• Cell Line, Tumor
• DNA Adducts
• DNA Primers (chemistry)
• DNA, Complementary (metabolism)
• Humans
• Hypoxia
• Lipid Peroxidation
• Microscopy, Fluorescence
• Mitochondria (metabolism, pathology)
• Nitric Oxide (metabolism)
• Oxidative Stress
• Oxygen (metabolism)
• RNA, Messenger (metabolism)
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Superoxide Dismutase (metabolism, physiology)
• Time Factors
• Transfection