title: Chelidonine suppresses migration and invasion of MDA-MB-231 cells by inhibiting formation of the integrin-linked kinase/PINCH/α-parvin complex.
abstract: Metastasis is the primary cause of cancer-associated mortality. The ternary IPP complex of integrin-linked kinase, PINCH and parvin functions as a signaling platform for integrins, which modulate numerous cellular processes including cell migration and invasion. Chelidonine, isolated from Chelidonium majus, is a benzophenanthridine alkaloid that exhibits anticancer properties; however, the anti-migratory and anti-invasive effects of chelidonine remain unknown. The aim of the present study was to investigate the inhibitory effects of chelidonine on migration and invasion of MDA-MB-231 human breast cancer cells, and to determine the underlying mechanisms. Chelidonine was shown to inhibit the migration and invasion of MDA-MB-231 cells in a concentration-dependent manner, without affecting the cell viability. Chelidonine did not significantly inhibit the adhesion of the cells to type 1 collagen (COL-I), however it did affect cell spreading and reorganization of the actin cytoskeleton. Chelidonine also inhibited COL-I-induced protein kinase B (Akt) activation and translocation to the plasma membrane, however, it did not significantly inhibit the activation of focal adhesion kinase. Notably, chelidonine treatment significantly inhibited COL-I-induced formation of the IPP complex and activation of IPP downstream signaling molecules, such as extracellular signal-regulated kinase (ERK)1/2. These results suggest that chelidonine exhibits anti-migratory and anti-invasive effects in MDA-MB-231 cells, by suppressing COL-I-induced integrin signaling, through inhibiting the formation of the IPP complex and subsequent down-regulation of IPP downstream signaling molecules, such as Akt and ERK1/2. These results suggest that chelidonine may be a potential therapeutic agent against metastasis of invasive human cancer cells.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon‑do 200‑701, Republic of Korea.
authors.forename: Okhwa
authors.initials: O
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon‑do 200‑701, Republic of Korea.
authors.forename: Cheol
authors.initials: C
authors.lastname: Hwangbo
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon‑do 200‑701, Republic of Korea.
authors.forename: Junhyeong
authors.initials: J
authors.lastname: Kim
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Yanbian University, Yanji, Jilin 133002, P.R. China.
authors.forename: Dong-Hao
authors.initials: DH
authors.lastname: Li
authors.affiliation: College of Pharmacy, Catholic University of Daegu, Gyeongsan, North Gyeongsang 712‑702, Republic of Korea.
authors.forename: Byung-Sun
authors.initials: BS
authors.lastname: Min
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon‑do 200‑701, Republic of Korea.
authors.forename: Jeong-Hyung
authors.initials: JH
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D053119:Benzophenanthridines / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000099200:Scaffold Protein ILK; D000096985:Calponins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D053119:Benzophenanthridines; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C088088:LIMS1 protein, human; C486590:PARVA protein, human; D000096985:Calponins; C062047:chelidonine