Cancer metastasis and EGFR signaling is suppressed by amiodarone-induced versican V2

Abstract

// Hung-Chieh Lee 1 , Mai-Yan Su 2 , Hao-Chan Lo 2 , Chin-Chieh Wu 3 , Jia-Rung Hu 1 , Dao-Ming Lo 2 , Tsu-Yi Chao 4 , Huai-Jen Tsai 1 , Ming-Shen Dai 3 1 Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan 2 Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University, Taipei, Taiwan 3 Hematology/Oncology, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan 4 Hematology/Oncology, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan Correspondence to: Ming-Shen Dai, e-mail: dms1201@gmail.com Keywords: amiodarone, versican, metastasis, EGFR signaling Received: April 19, 2015      Accepted: October 09, 2015      Published: October 21, 2015 ABSTRACT Extracellular matrix components play an active role in cancer progression and prognosis. Versican, a large extracellular matrix proteoglycan, can promote cancer metastasis through facilitating cell proliferation, adhesion, migration and angiogenesis. We had previously demonstrated that amiodarone caused ectopic overexpression of similar to versican b ( s-vcanb ), inhibited EGFR/GSK3β/Snail signaling, and enhanced Cdh5 at the heart field of zebrafish, indicating interference with epithelial-mesenchymal transition (EMT). Since S-vcanb is homologous to mammalian versican V2 isoform, we examined the effects of amiodarone on mammalian tumor proliferation, migration, invasion and metastasis in vitro and in vivo and on EMT signaling pathways. Monolayer wound assays and extracellular matrix transwell invasion assays showed reduced migration and invasion by 15 μM amiodarone treated B16OVA, JC, 4T-1, MDA-MB-231 and MCF-7 tumor cell lines. All cancer cell lines showed reduced metastatic capabilities in vivo after treatment with amiodarone in experimental animals. Western blots revealed that EMT-related transcription factors Snail and Twist were reduced and E-cadherin was enhanced in amiodarone treated cells through an EGFR/ERK/GSK3β-dependent pathway. Immunohistochemistry showed amiodarone lead to increased expression of versican V2 isoform concomitant with reduced versican V1. Our study illustrated the role of versican v2 in EMT modulation and cancer suppression by amiodarone treatment.