101. 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
- Author
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Ching Wen Chang, Ting Wei Lin, Sen Je Sheu, Shiu Huey Chou, Jeng Fan Lo, Yu Syuan Chen, Te-Chang Lee, Chien Chih Chen, Chung Ji Liu, Ik On Chan, and Chin Chu Chen
- Subjects
0301 basic medicine ,Homeobox protein NANOG ,STAT3 Transcription Factor ,Cell Survival ,Cellular differentiation ,Cell ,Antineoplastic Agents ,Models, Biological ,STAT3 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Ascomycota ,cancer initiating cells ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cell Self Renewal ,Cytotoxicity ,Cholestenones ,Cisplatin ,business.industry ,Cell Differentiation ,Drug Synergism ,differentiation ,medicine.disease ,Head and neck squamous-cell carcinoma ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,ergone ,src-Family Kinases ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Neoplastic Stem Cells ,business ,Antrodia cinnamomea ,medicine.drug ,Research Paper ,Src - 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.
- Published
- 2016