Paraoxonase-1 (PON1) induces metastatic potential and apoptosis escape via its antioxidative function in lung cancer cells
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Mark Borris D. Aldonza1,3,*, Yeon Sung Son1,*, Hye-Jin Sung1, Jung Mo Ahn1,4, Young-Jin Choi1,5, Yong-In Kim1, Sukki Cho2 and Je-Yoel Cho1
1Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
2Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seoungnam-Si, Gyeonggi-Do, Republic of Korea
3Current address: Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
4Current address: Bio Center, Incheon Technopark, Incheon, Republic of Korea
5Current address: College of Medicine, University of Ulsan, Seoul, Republic of Korea
*These authors have contributed equally to this work
Je-Yoel Cho, email: email@example.com
Keywords: paraoxonase-1, PON1, lung cancer, cell death, HDL
Received: February 15, 2017 Accepted: March 20, 2017 Published: April 12, 2017
Paraoxonase-1 (PON1) gene polymorphisms have been closely associated with the development of advanced cancers while PON1 secretion to the serum is linked with inhibition of oxidized high-density lipoprotein by its antioxidative function. Our group previously demonstrated that post-translational modification of serum PON1 in form of fucosylated PON1 is a potential biomarker of small cell lung cancer. Here, we interrogated the role of PON1 in the pathobiology of lung cancer (LC) by addressing cell-autonomous mechanisms using gain-of-function and loss-of-function approaches and protein expression profiling of tissue samples in our clinical biobank. PON1 expression in LC patient tissues varied between overexpression in squamous cell carcinoma and minimal loss in adenocarcinoma sub-types. Simultaneous overexpression of PON1 both at the gene and protein stability levels induced pro-oncogenic characteristics in LC cells and xenografts. PON1 overexpression supported metastatic progression of LC by decreasing G1/S ratio and LC cell senescence involving p21Waf1/Cip1. PON1 suppressed drug- and ligand-induced cell death and protected LC cells from genotoxic damages with maintained ATP levels, requiring p53-directed signals. PON1 promoted ROS deregulation protecting the mitochondria from dysregulation. PON1 knockdown resulted in the blockage of its antioxidant function in LC cells through Akt signaling with reduced invasive signature as a consequence of scant expression. Targeted glycolysis stimulated PON1 antioxidant activity regulating phosphorylation of AMPK-α. The functional data imply that exploitation of the antioxidative function of PON1 is consequential in driving LC pathogenesis at the cell-autonomous mechanistic level with consequences on tumor growth.
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