PT  - JOURNAL ARTICLE
AU  - Ling-Ming Tseng
AU  - Pin-I Huang
AU  - Yu-Rung Chen
AU  - Yu-Chih Chen
AU  - Yueh-Ching Chou
AU  - Yi-Wei Chen
AU  - Yuh-Lih Chang
AU  - Han-Shui Hsu
AU  - Yuan-Tzu Lan
AU  - Kuan-Hsuan Chen
AU  - Chin-Wen Chi
AU  - Shih-Hwa Chiou
AU  - De-Ming Yang
AU  - Chen-Hsen Lee
TI  - Targeting Signal Transducer and Activator of Transcription 3 Pathway by Cucurbitacin I Diminishes Self-Renewing and Radiochemoresistant Abilities in Thyroid Cancer-Derived CD133<sup>+</sup> Cells
AID  - 10.1124/jpet.111.188730
DP  - 2012 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 410--423
VI  - 341
IP  - 2
4099  - http://jpet.aspetjournals.org/content/341/2/410.short
4100  - http://jpet.aspetjournals.org/content/341/2/410.full
SO  - J Pharmacol Exp Ther2012 May 01; 341
AB  - Anaplastic thyroid cancer (ATC) is a lethal solid tumor with poor prognosis because of 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 thyroid cancer-related CSCs 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 with ATC-CD133− cells. Microarray bioinformatics analysis suggested that the signal transducer and activator of transcription 3 (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. Of note, treatment of ATC-CD133+ cells with cucurbitacin I up-regulated 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.