Alteration of APE1/ref-1 expression in non-small cell lung cancer: the implications of impaired extracellular superoxide dismutase and catalase antioxidant systems.
OBJECTIVE
Apurinic/apyrimidinic endonuclease1/ref-1(APE1/ref-1) is a key enzyme in the base excision repair and in transcriptional modulation against oxidative stress. We investigated the altered expression of APE1/ref-1 and antioxidant systems in lung cancer.


METHODS
Tumor specimens from 48 patients with operable non-small cell lung cancer were obtained from 2004 to 2006. Immunohistochemistry, Western blot, lipid peroxidation and superoxide production were performed on the tumor samples and a cultured H460 cell line.


RESULTS
APE1/ref-1 was mainly localized to the nucleus in the non-tumor regions of the lung cancer tissue specimens. However, nuclear and cytoplasmic expressions of APE1/ref-1 in the lung cancers were markedly up-regulated in the non-small cell lung cancer (NSCLC) specimens including squamous cell and adenocarcinoma specimens. Extracellular superoxide dismutase (ECSOD) and catalase were down-regulated and manganese superoxide dismutase (MnSOD) was up-regulated in the tumor regions of the NSCLC. Tumor regions of the NSCLC showed higher superoxide production and lipid peroxidation levels than non-tumor regions. In the lung adenocarcinoma cell line, H460, treatment with hydrogen peroxide in the presence of a catalase inhibitor, aminotriazole, increased APE1/ref-1 expression, suggesting oxidative stress might have contributed to the induction of APE1/ref-1.


CONCLUSIONS
The results of this study suggest that APE1/ref-1 is up-regulated in the tumor regions of NSCLC. Altered expression of antioxidant systems lead to enhanced production of superoxide production and lipid peroxidation, which can induce APE1/ref-1 in the tumor regions of NSCLS.
Department of Physiology, College of Medicine, Chungnum National University, Jung-gu, Daejeon 301-131, Republic of Korea.
Dae Goon
DG
Yoo
Yun Jeong
YJ
Song
Eun Jung
EJ
Cho
Sang Ki
SK
Lee
Jin Bong
JB
Park
Jae Hyeon
JH
Yu
Seung Pyung
SP
Lim
Jin Man
JM
Kim
Byeong Hwa
BH
Jeon
D000368:Aged; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis*; D045604:Extracellular Fluid / Q000201:enzymology*; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology; D008175:Lung Neoplasms / Q000378:metabolism*; D008315:Malondialdehyde / Q000378:metabolism; D008875:Middle Aged; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000032:analysis
D000975:Antioxidants; D013481:Superoxides; D008315:Malondialdehyde; D002374:Catalase; D013482:Superoxide Dismutase; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase