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Subcellular localization of apurinic endonuclease 1 promotes lung tumor aggressiveness via NF-κB activation

Oncogene volume 29, pages 4330–4340 (2010)Cite this article

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Abstract

Apurinic endonuclease 1 (Ape1) is not only involved in base excision repair, but also activates some transcriptional factors through its redox activity. However, which subcellular localization of Ape1 is involved in the activation of transcriptional factor remains unclear. We first observed that Cox-2 expression was associated with cytoplasmic Ape1 expression in lung tumors and cancer cell lines. We thus hypothesize that nuclear factor (NF)-κB is activated by cytoplasmic Ape1 to cause Cox-2 expression. Herein, we generated cytoplasmic and nuclear Ape1 in Ape1-knockdown lung cancer cells by exogenous expression of Ape1 containing various deletions and/or mutations of the nuclear localization sequence. It was observed that cytoplasmic Ape1, but not nuclear Ape1, induced Cox-2 expression through NF-κB activation. NF-κB activation by cytoplasmic Ape1 was diminished by the Ape1 redox activity inhibitor resveratrol. Cells expressing cytoplasmic Ape1 exhibited tumor progression and metastasis in vitro and in vivo as xenografts, but cells expressing nuclear Ape1 did not. Patients with tumors containing elevated cytoplasmic Ape1 had a poor prognosis and a 3.722-fold risk of tumor recurrence and/or metastasis. Cytoplasmic Ape1 could therefore enhance lung tumor malignancy through NF-κB activation, suggesting that combination of cisplatin and specific redox inhibitor could improve chemotherapeutic response in patients with tumors containing elevated cytoplasmic Ape1.

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Acknowledgements

This work was jointly supported by grants from the National Health Research Institute (NHRI96-TD-G-111-006; NHRI97-TD-G-111-006) and the National Science Council (NSC-96-2628-B-040-002-MY3) of Taiwan, ROC.

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Authors and Affiliations

  1. Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, Republic of China

    H-H Wu, J T Chang & H Lee

  2. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China

    Y-W Cheng & H Lee

  3. Division of Chest Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China

    T-C Wu

  4. Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China

    W-S Liu

  5. Department of Surgery, China Medical University Hospital, Taichung, Taiwan, Republic of China

    C-Y Chen

  6. Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan, Republic of China

    H Lee

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Wu, HH., Cheng, YW., Chang, J. et al. Subcellular localization of apurinic endonuclease 1 promotes lung tumor aggressiveness via NF-κB activation. Oncogene 29, 4330–4340 (2010). https://doi.org/10.1038/onc.2010.178

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