Targeting cancer initiating cells by promoting cell differentiation and restoring chemosensitivity via dual inactivation of STAT3 and Src activity using an active component of Antrodia cinnamomea mycelia

// Ching-Wen Chang 1, * , Yu-Syuan Chen 1, * , Chien-Chih Chen 2, * , Ik-On Chan 1 , Chin-Chu Chen 3 , Sen-Je Sheu 3 , Ting-wei Lin 3 , Shiu-Huey Chou 4 , Chung-Ji Liu 5 , Te-Chang Lee 6 , Jeng-Fan Lo 1, 7, 8, 9 1 Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan 2 Department of Biotechnology, Hungkuang University, Taichung, Taiwan 3 Grape King Inc., Taoyuan County, Taiwan 4 Department of Life Science, Fu-Jen University, Taipei, Taiwan 5 Department of Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei, Taiwan 6 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 7 Graduate Institute of Chinese Medical Science and Institute of Medical Science, China Medical University, Taichung, Taiwan 8 Genome Research Center, National Yang-Ming University, Taipei, Taiwan 9 Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan * These authors contributed equally to this work Correspondence to: Jeng-Fan Lo, email: jflo@ym.edu.tw Keywords: ergone, cancer initiating cells, STAT3, Src, differentiation Received: April 08, 2016      Accepted: September 14, 2016      Published: September 22, 2016 ABSTRACT Cancer initiating cells (CICs) represent a subpopulation of cancer cells, which are responsible for tumor growth and resistance to chemotherapy. Herein, we first used a cell-based aldehyde dehydrogenase (ALDH) activity assay to identify that YMGKI-2 (also named as Ergone), an active component purified from Antrodia cinnamomea Mycelia extract (ACME), effectively abrogated the ALDH activity and abolished the CICs in head and neck squamous cell carcinoma cells (HNSCCs). Consequently, YMGKI-2 treatment suppressed self-renewal ability and expression of stemness signature genes (Oct-4 and Nanog) of sphere cells with enriched CICs. Moreover, YMGKI-2 treated sphere cells displayed reduction of CICs properties and promotion of cell differentiation, but not significant cytotoxicity. YMGKI-2 treatment also attenuated the tumorigenicity of HNSCC cells in vivo . Mechanistically, treatment of YMGKI-2 resulted in inactivation of STAT3 and Src. Lastly, combinatorial treatments with YMGKI-2 and standard chemotherapeutic drugs (cisplatin or Fluorouracil) restored the chemosensivity on sphere cells and cisplatin-resistant HNSCC cells. Together, we demonstrate that YMGKI-2 treatment effectively induces differentiation and reduces tumorigenicity of CICs. Further, combined treatment of YMGKI-2 and conventional chemotherapy can overcome chemoresistance. These results suggest that YMGKI-2 treatment may be used to improve future clinical responses in head and neck cancer treatment through targeting CICs.