NOX4 promotes non-small cell lung cancer cell proliferation and metastasis through positive feedback regulation of PI3K/Akt signaling
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Cuixiang Zhang1,2,*, Tian Lan3,*, Jincai Hou1,2, Juan Li4,5, Rende Fang4,5, Zhicheng Yang4, Min Zhang6, Jianxun Liu1,2 and Bing Liu4,5
1 Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 110300, China
2 Beijing Key Laboratory of Pharmacology of Chinese Materia Medica, Beijing110300, China
3 Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China
4 Department of Clinical pharmacy, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
5 Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China
6 Department of health statistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510006, China
* These Authors contributed equally to this work
Bing Liu, email:
Jianxun Liu, email:
Keywords: NOX4; non-small cell lung cancer; proliferation; metastasis; PI3K/Akt signaling
Received: March 27, 2014 Accepted: May 27, 2014 Published: May 28, 2014
NADPH oxidase 4 (NOX4) is deregulated in various cancers and involved in cancer proliferation and metastasis. However, what the role of NOX4 plays during malignant progression of non-small cell lung cancer (NSCLC) remains unknown. Our results show that NOX4 was upregulated in NSCLC cell lines and samples from patients, compared with controls; NOX4 protein levels were closely correlated with clinical disease stage and survival time. Overexpression of NOX4 in A549 and H460 NSCLC cells enhanced cell proliferation and invasion in vitro, and produced larger tumors, shorter survival time, and more lung metastasis in nude mice than control cells. On the contrary, NOX4 depletion inhibited NSCLC cell aggressiveness. Inhibition of PI3K/Akt pathway could sufficiently block the cellular effects of NOX4 overexpression in NSCLC cells both in vitro and in vivo. Specifically, we demonstrated that PI3K/Akt pathway also positively regulated NOX4 expression via NF-κB-mediated manner. Therefore, there existed a mutual positive regulation between NOX4 and PI3K/Akt signaling in NSCLC cells, and NOX4 was confirmed to functionally interplay with PI3K/Akt signaling to promote NSCLC cell proliferation and invasion. In conclusion, the positive feedback loop between NOX4 and PI3K/Akt signaling contributes to NSCLC progression.
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