Research Papers:

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, Yu-Syuan Chen, Chien-Chih Chen, Ik-On Chan, Chin-Chu Chen, Sen-Je Sheu, Ting-wei Lin, Shiu-Huey Chou, Chung-Ji Liu, Te-Chang Lee and Jeng-Fan Lo _

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Oncotarget. 2016; 7:73016-73031. https://doi.org/10.18632/oncotarget.12194

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Ching-Wen Chang1,*, Yu-Syuan Chen1,*, Chien-Chih Chen2,*, Ik-On Chan1, Chin-Chu Chen3, Sen-Je Sheu3, Ting-wei Lin3, Shiu-Huey Chou4, Chung-Ji Liu5, Te-Chang Lee6, Jeng-Fan Lo1,7,8,9

1Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan

2Department of Biotechnology, Hungkuang University, Taichung, Taiwan

3Grape King Inc., Taoyuan County, Taiwan

4Department of Life Science, Fu-Jen University, Taipei, Taiwan

5Department of Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei, Taiwan

6Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

7Graduate Institute of Chinese Medical Science and Institute of Medical Science, China Medical University, Taichung, Taiwan

8Genome Research Center, National Yang-Ming University, Taipei, Taiwan

9Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan

*These authors contributed equally to this work

Correspondence to:

Jeng-Fan Lo, email: [email protected]

Keywords: ergone, cancer initiating cells, STAT3, Src, differentiation

Received: April 08, 2016     Accepted: September 14, 2016     Published: September 22, 2016


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.

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