Doxycycline reverses epithelial-to-mesenchymal transition and suppresses the proliferation and metastasis of lung cancer cells

Abstract

// Yuan Qin 1, 2, * , Qiang Zhang 1, 2, * , Shan Lee 1, 2, * , Wei-long Zhong 1, 2, * , Yan-rong Liu 2 , Hui-juan Liu 2 , Dong Zhao 1, 2 , Shuang Chen 2 , Ting Xiao 1, 2 , Jing Meng 1, 2 , Xue-shuang Jing 2 , Jing Wang 2 , Bo Sun 2 , Ting-ting Dai 2 , Cheng Yang 1, 2 , Tao Sun 1, 2 , Hong-gang Zhou 1, 2 1 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China 2 Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China * These authors have contributed equally to this work Correspondence to: Tao Sun, e-mail: sunrockmia@hotmail.com Hong-gang Zhou, e-mail: honggang.zhou@vip.126.com Keywords: doxycycline, antitumor, EMT, metastasis, lung cancer Received: July 11, 2015      Accepted: September 24, 2015      Published: October 14, 2015 ABSTRACT The gelatinase inhibitor doxycycline is the prototypical antitumor antibiotic. We investigated the effects of doxycycline on the migration, invasion, and metastasis of human lung cancer cell lines and in a mouse model. We also measured the effect of doxycycline on the transcription of epithelial-mesenchymal transition (EMT) markers, and used immunohistochemistry to determine whether EMT reversal was associated with doxycycline inhibition. Doxycycline dose-dependently inhibited proliferation, migration, and invasion of NCI-H446 human small cell lung cancer cells. It also suppressed tumor growth from NCI-H446 and A549 lung cancer cell xenografts without altering body weight, inhibited Lewis lung carcinoma cell migration, and prolonged survival. The activities of the transcription factors Twist1/2, SNAI1/2, AP1, NF-κB, and Stat3 were suppressed by doxycycline, which reversed EMT and inhibited signal transduction, thereby suppressing tumor growth and metastasis. Our data demonstrate functional targeting of transcription factors by doxycycline to reverse EMT and suppress tumor proliferation and metastasis. Thus, doxycycline selectively targets malignant tumors and reduces its metastatic potential with less cytotoxicity in lung cancer patients.