May 26, 2010

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

Oncogene
H-H WuH Lee

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)-kappaB 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-kappaB activation. NF-kappaB 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 Ape...Continue Reading

Mentioned in this Paper

Establishment and Maintenance of Localization
Cyclooxygenase 2
Positive Regulation of NF-kappaB Transcription Factor Activity
Mice, Inbred BALB C
Oxidation-Reduction Activity [MoA]
DNA-(apurinic or apyrimidinic site) lyase
Protoplasm
Transcription, Genetic
Base Excision Repair
Neoplasms

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