Daurinol blocks breast and lung cancer metastasis and development by inhibition of focal adhesion kinase (FAK)

// Jong Kyu Woo 1, 2 , Hyun Jin Jung 2 , Ji-Youn Park 1 , Ju-Hee Kang 1 , Byung Il Lee 3 , DongYun Shin 1 , Chu Won Nho 4 , Soo-Young Cho 3 , Je Kyung Seong 2, * and Seung Hyun Oh 1, * 1 Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea 2 Korea Mouse Phenotyping Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea 3 National Cancer Center, Goyang-si, Republic of Korea 4 Korea Institute of Science and Technology (KIST), Gangneung Institute, Gangneung-si, Republic of Korea * These are authors contributed equally to this work Correspondence to: Seung Hyun Oh, email: eyeball@hanmail.net , eyeball@gachon.ac.kr Keywords: daurinol, breast cancer, lung cancer, FAK, metastasis Received: January 16, 2017      Accepted: June 18, 2017      Published: July 04, 2017 ABSTRACT FAK overexpression has been reported in diverse primary and metastatic tumor tissues, supporting its pro-tumorigenic and pro-metastatic roles. Therefore, we have developed a neo-treatment strategy using daurinol to effectively treat cancer metastasis. Daurinol blocked cancer cell migration and invasion in vitro and exhibited anti-metastatic activity in an experimental metastasis model of breast and lung cancer. Daurinol selectively inhibited phosphorylation of FAK at Tyr925, Tyr576/577, and Tyr397 sites in a dose- and time-dependent manner. Daurinol effectively suppressed migration and invasion of MDA-MB-231 and A549 cancer cells. These data were associated with inhibition of expression and secretion of invasion factors, including matrix metalloproteinase (MMP) 2, MMP9, and urokinase plasminogen activator (uPA). Consistent with these in vitro results, daurinol (10 mg/kg; Oral gavage) effectively inhibited breast and lung cancer metastasis in a mouse model. In addition, daurinol showed strong suppressive activity of cell survival as revealed by colony formation assays. Analysis of cellular phenotypes revealed that inhibition of FAK phosphorylation in cancer cells limited colony formation, cell migration, and invasion, thereby reducing the cell proliferation rate. Furthermore, daurinol significantly reduced tumor development in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)/benzo(a)pyrene (BaP)-treated A/J mice. Our results suggest that daurinol suppresses lung metastasis through inhibition of migration and survival via blockade of FAK activity.