Resveratrol inhibits human lung adenocarcinoma cell metastasis by suppressing heme oxygenase 1-mediated nuclear factor-kappaB pathway and subsequently downregulating expression of matrix metalloproteinases.
Resveratrol exhibits potential anti-carcinogenic activities. Heme oxygenase-1 (HO-1) is involved in angiogenesis and tumor metastasis. Matrix metalloproteinases (MMPs) are key enzymes in the degradation of extracellular matrix, and their expression may be dysregulated in lung cancer metastasis. In this study, we investigated the anti-invasive mechanism of resveratrol in lung cancer cells. HO-1 was shown to be elevated (approximately 4.7-fold) in lung cancer tumor samples as compared with matched normal tissues. After treatment of lung adenocarcinoma cell line A549 cells with resveratrol (50 microM) for 24 h, the migratory and invasive abilities (38 and 30% inhibition, respectively) of A549 cells were significantly reduced. Resveratrol significantly inhibited HO-1-mediated MMP-9 (35% inhibition) and MMP-2 (28% inhibition) expression in lung cancer cells. Nuclear factor (NF)-kappaB inhibitor induced a marked reduction in MMP-9 and MMP-2 expression, suggesting NF-kappaB pathway could play an important role. Furthermore, HO-1 inhibition and silencing significantly suppressed MMPs and invasion of lung cancer cells. Our results suggest that resveratrol inhibited HO-1 and subsequently MMP-9 and MMP-2 expression in lung cancer cells. The inhibitory effects of resveratrol on MMP expression and invasion of lung cancer cells are, in part, associated with the HO-1-mediated NF-kappaB pathway.
Liu
Po-Len
PL
Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Tsai
Jong-Rung
JR
Charles
Albert Linton
AL
Hwang
Jhi-Jhu
JJ
Chou
Shah-Hwa
SH
Ping
Yueh-Hsin
YH
Lin
Feng-Yen
FY
Chen
Yuh-Lien
YL
Hung
Chun-Ying
CY
Chen
Wen-Chi
WC
Chen
Yung-Hsiang
YH
Chong
Inn-Wen
IW
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D009994:Osmolar Concentration; D034741:RNA, Small Interfering; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D034741:RNA, Small Interfering; D013267:Stilbenes; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D020782:Matrix Metalloproteinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000077185:Resveratrol