title: Rho-associated kinase signaling is required for osteopontin-induced cell invasion through inactivating cofilin in human non-small cell lung cancer cell lines.
abstract: Osteopontin (OPN) is involved in tumor progression such as invasion and metastasis, and poor prognosis of lung cancer. However, how OPN affects the invasive behavior of lung cancer is not well defined. Here, we examined the underlying molecular mechanism of OPN-induced invasion in human non-small cell lung cancer (NSCLC) cell lines including A549 cells. OPN markedly increased the phosphorylation of LIM kinase 1 and 2 (LIMK1/2), and cofilin without affecting their total forms. The expression of Rho-associated kinase 1 (ROCK1), but not p21-activated kinase 1 and 2 (PAK1/2), was increased by OPN treatment as an upstream effector of LIMK/cofilin. The phosphorylation of cofilin by OPN was suppressed when cells were pretreated with ROCK inhibitor Y27632 by Western blot. Moreover, it verified that OPN inactivated cofilin through ROCK signaling in other NSCLC cell lines. OPN induced the phosphorylation of FAK and AKT. FAK inhibitor FAKi-14 and PI3K inhibitor wortmannin decreased the expressions of ROCK1, and phosphorylation of LIMK1/2 and cofilin. OPN caused a significant increase in the lamellipodia formation and cell invasion, and these are suppressed by FAK inhibitor FAKi-14, PI3K inhibitor wortmannin and ROCK inhibitor Y27632. Taken together, these results suggest that OPN triggers ROCK signaling mediated by FAK/PI3K/AKT pathway, which in turn induces the lamellipodia formation to allow the invasion of lung cancer cells through inactivating cofilin.
authors: Cancer Preventive Material Development Research Center, College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors: Chi Gu
authors: CG
authors: Kang
authors: Cancer Preventive Material Development Research Center, College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors: Hwa Jeong
authors: HJ
authors: Han
authors: Cancer Preventive Material Development Research Center, College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors: Hyo-Jeong
authors: HJ
authors: Lee
authors: Cancer Preventive Material Development Research Center, College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors: Sung-Hoon
authors: SH
authors: Kim
authors: Cancer Preventive Material Development Research Center, College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea. Electronic address: leook@khu.ac.kr.
authors: Eun-Ok
authors: EO
authors: Lee
mesh_terms: D051339:Actin Depolymerizing Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D053495:Osteopontin / Q000378:metabolism* / Q000494:pharmacology; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D053495:Osteopontin; D054460:rho-Associated Kinases
keywords: A549 cells; AKT; Cofilin; FAK; Invasion; Lamellipodia; NSCLC; Osteopontin; PI3K; ROCK1