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Cancer stem-like cells from head and neck cancers are chemosensitized by the Wnt antagonist, sFRP4, by inducing apoptosis, decreasing stemness, drug resistance and epithelial to mesenchymal transition.
Warrier, S; Bhuvanalakshmi, G; Arfuso, F; Rajan, G; Millward, M; Dharmarajan, A.
Afiliación
  • Warrier S; 1] Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal University, Bangalore, India [2] Faculty of Health Sciences, School of Biomedical Sciences, Curtin University, Perth, Western Australia.
  • Bhuvanalakshmi G; Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal University, Bangalore, India.
  • Arfuso F; 1] Faculty of Health Sciences, School of Biomedical Sciences, Curtin University, Perth, Western Australia [2] School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, Western Australia.
  • Rajan G; School of Surgery, The University of Western Australia, Perth, Western Australia.
  • Millward M; School of Medicine and Pharmacology, The University of Western Australia, Perth, Western Australia.
  • Dharmarajan A; Faculty of Health Sciences, School of Biomedical Sciences, Curtin University, Perth, Western Australia.
Cancer Gene Ther ; 21(9): 381-8, 2014 Sep.
Article en En | MEDLINE | ID: mdl-25104726
Cancer stem cells (CSCs) of head and neck squamous cell carcinoma (HNSCC) are defined by high self-renewal and drug refractory potential. Involvement of Wnt/ß-catenin signaling has been implicated in rapidly cycling cells such as CSCs, and inhibition of the Wnt/ß-catenin pathway is a novel approach to target CSCs from HNSCC. In this study, we found that an antagonist of FrzB/Wnt, the secreted frizzled-related protein 4 (sFRP4), inhibited the growth of CSCs from two HNSCC cell lines, Hep2 and KB. We enriched the CD44(+) CSC population, and grew them in spheroid cultures. sFRP4 decreased the proliferation and increased the sensitivity of spheroids to a commonly used drug in HNSCC, namely cisplatin. Self-renewal in sphere formation assays decreased upon sFRP4 treatment, and the effect was reverted by the addition of Wnt3a. sFRP4 treatment of spheroids also decreased ß-catenin, confirming its action through the Wnt/ß-catenin signaling pathway. Quantitative PCR demonstrated a clear decrease of the stemness markers CD44 and ALDH, and an increase in CD24 and drug-resistance markers ABCG2 and ABCC4. Furthermore, we found that after sFRP4 treatment, there was a reversal in the expression of epithelial to mesenchymal (EMT) markers with the restoration of the epithelial marker E-cadherin, and depletion of EMT-specific markers twist, snail and N-cadherin. This is the first report demonstrating that the naturally occurring Wnt inhibitor, sFRP4, can be a potential drug to destroy CSC-enriched spheroids from HNSCCs. The repression of EMT and the decrease in stemness profile further strengthen the use of sFRP4 as a potent therapeutic against CSCs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Proteínas Proto-Oncogénicas / Apoptosis / Proteínas Wnt / Neoplasias de Cabeza y Cuello Límite: Humans Idioma: En Revista: Cancer Gene Ther Asunto de la revista: GENETICA MEDICA / NEOPLASIAS / TERAPEUTICA Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Proteínas Proto-Oncogénicas / Apoptosis / Proteínas Wnt / Neoplasias de Cabeza y Cuello Límite: Humans Idioma: En Revista: Cancer Gene Ther Asunto de la revista: GENETICA MEDICA / NEOPLASIAS / TERAPEUTICA Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido