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Targeting STAT3 Pathway by Cucurbitacin I Diminishes Self-renewaling and Radiochemoresistant Abilities in Thyroid Cancer-derived CD133+ Cells.
MedLine Citation:
PMID:  22328572     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Anaplastic thyroid cancer (ATC) is a lethal solid tumor with poor prognosis due to its invasiveness and its resistance to current therapies. Recently, ATC-CD133(+) cells were found to have cancer stem cell (CSC) properties and were suggested to be important contributors to tumorigenicity and cancer metastasis. However, the molecular pathways and therapeutic targets in TC-related CSC remain undetermined. In this study, ATC-CD133(+) cells were isolated and found to have increased tumorigenicity, radioresistance, and higher expression of both embryonic stem cell-related and drug resistance-related genes compared to ATC-CD133(-) cells. Microarray bioinformatics analysis suggested that the STAT3 pathway could be important in regulating the stemness signature in ATC-CD133(+) cells; therefore, the effect of the potent STAT3 inhibitor cucurbitacin I in ATC-CD133(+) cells was evaluated in this study. Treatment of ATC-CD133(+) cells with cucurbitacin I diminished their CSC-like abilities, inhibited their stemness gene signature, and facilitated their differentiation into ATC-CD133(-) cells. Notably, treatment of ATC-CD133(+) cells with cucurbitacin I upregulated the expression of thyroid-specific genes and significantly enhanced radioiodine uptake. Furthermore, cucurbitacin I treatment increased the sensitivity of ATC-CD133(+) cells to radiation and chemotherapeutic drugs through apoptosis. Finally, xenotransplantation experiments revealed that cucurbitacin I plus radiochemotherapy significantly suppressed tumorigenesis and improved survival in immunocompromised mice into which ATC-CD133(+) cells were transplanted. In summary, these results show that the STAT3 pathway plays a key role in mediating CSC properties in ATC-CD133(+) cells. Targeting STAT3 with cucurbitacin I in ATC may provide a new approach for therapeutic treatment in the future.
Authors:
Ling-Ming Tseng; Pin-I Huang; Yu-Rung Chen; Yu-Chih Chen; Yueh-Ching Chou; Yi-Wei Chen; Yuh-Lih Chang; Han-Shui Hsu; Yuan-Tzu Lan; Kuan-Hsuan Chen; Chin-Wen Chi; Shih-Hwa Chiou; De-Ming Yang; Chen-Hsen Lee
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-2-10
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  -     ISSN:  1521-0103     ISO Abbreviation:  -     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-2-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1 Taipei Veterans General Hospital;
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