Pterostilbene prevents AKT-ERK axis-mediated polymerization of surface fibronectin on suspended lung cancer cells independently of apoptosis and suppresses metastasis.
Polymeric fibronectin (polyFN) assembled on suspended breast cancer cells is required for metastasis. Conceivably, drugs that target such polyFN may fight against cancer metastasis. While stilbene analogs trigger pro-apoptotic effect on attached cancer cells, whether they prevent polyFN assembly and metastasis of suspended cancer cells via an apoptosis-independent manner remains unexplored.



We depleted suspended Lewis lung carcinoma (LLC) cells of polyFN by silencing the endogenous FN expression or pterostilbene (PS) to examine whether metastasis of lung cancer cells could thus be suppressed. We investigated whether PS regulates AKT-ERK signaling axis to suppress polyFN assembly in suspended LLC cells independently of apoptosis. We tested the therapeutic effects of orally administered PS against cancer metastasis.



Both FN-silencing and PS among the three stilbenoids indeed significantly reduced polyFN assembly and lung metastasis of suspended LLC cells in an apoptosis-independent manner. Mechanistically, PS-induced AKT phosphorylation (pAKT) and suppressed ERK phosphorylation (pERK) in suspended LLC cells, whereas pretreatment with a PI3K inhibitor, LY294002, effectively reduced pAKT, rescued pERK, and consequently reversed the PS-suppressed polyFN assembly on LLC cells; these pretreatment effects were then overturned by the ERK inhibitor U0126. Indeed, PS-suppressed lung metastasis was counteracted by LY294002, which was further overruled with U0126. Finally, we found that PS, when orally administered in experimental metastasis assays, both significantly prevented lung colonization and metastasis of LLC cells and reduced the already established tumor growth in the mouse lungs.



PS suppressed AKT/ERK-regulated polyFN assembly on suspended LLC cells and pulmonary metastasis. PS possesses potency in both preventing and treating lung metastasis of lung cancer cells in apoptosis-independent and apoptosis-dependent manners, respectively.
Department of Environmental and Occupational Health, National Cheng Kung University, 1 University Road, 70101, Tainan, Taiwan.|Department of Biomedical Informatics, Asia University, Taichung, Taiwan.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.|Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
Ying-Jan
YJ
Wang
Department of Environmental and Occupational Health, National Cheng Kung University, 1 University Road, 70101, Tainan, Taiwan.
Jing-Fang
JF
Lin
The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Road, 70101, Tainan, Taiwan.
Li-Hsin
LH
Cheng
The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Road, 70101, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, 1 University Road, 70101, Tainan, Taiwan.
Wen-Tsan
WT
Chang
Department of Medical Research, E-Da Hospital, 82445, Kaohsiung, Taiwan.
Ying-Hsien
YH
Kao
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, 1 University Road, 70101, Tainan, Taiwan.
Ming-Min
MM
Chang
Department of Environmental and Occupational Health, National Cheng Kung University, 1 University Road, 70101, Tainan, Taiwan.|Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.|Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Bour-Jr
BJ
Wang
The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Road, 70101, Tainan, Taiwan. hungchi@mail.ncku.edu.tw.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, 1 University Road, 70101, Tainan, Taiwan. hungchi@mail.ncku.edu.tw.
Hung-Chi
HC
Cheng
D000818:Animals; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D020935:MAP Kinase Signaling System; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000517:prevention & control*; D058105:Polymerization / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use
D005353:Fibronectins; D013267:Stilbenes; C107773:pterostilbene; D051057:Proto-Oncogene Proteins c-akt
Fibronectin; PI3K/AKT/ERK signaling; Pericellular assembly; Pterostilbene; Pulmonary localization