Abstract
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.
Footnotes
This work was supported by the Division of Experimental Surgery of the Department of Surgery, Taipei Veterans General Hospital, the National Science Council [Grants 97-3111-B-075-001-MY3, 98-2314-B-341-001-MY3]; Taipei Veterans General Hospital [Grants V97B1-006, E1-008, ER2-018, ER3-005, F-001]; the Joint Projects of the University System of Taiwan and Taipei Veterans General Hospital [VGHUST 98-G6-6]; Yen-Tjing-Ling Medical Foundation; and National Yang-Ming University (Ministry of Education, Aim for the Top University Plan).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- PTC
- papillary thyroid cancer
- ATC
- anaplastic thyroid cancer
- CSC
- cancer stem cell
- STAT3
- signal transducer and activator of transcription 3
- MMP-9
- matrix metalloproteinase 9
- RET/PTC
- rearranged in transformation/papillary thyroid carcinoma
- p-STAT3
- phosphorylated STAT3
- DMEM
- Dulbecco's modified Eagle's medium
- bFGF
- basic fibroblast growth factor
- EGF
- epidermal growth factor
- IR
- ionizing radiation
- RT
- reverse transcriptase
- PCR
- polymerase chain reaction
- NIS
- sodium/iodide symporter
- GFP
- green fluorescent protein
- JAK
- Janus tyrosine kinase
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
- TPO
- thyroperoxidase
- Tg
- thyroglobulin
- PPARγ
- peroxisome proliferator-activated receptor-γ
- 5-FU
- 5-fluorouracil.
- Received October 7, 2011.
- Accepted February 9, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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