Targeting signal transducer and activator of transcription 3 pathway by cucurbitacin I diminishes self-renewing and radiochemoresistant abilities in thyroid cancer-derived CD133 + cells

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

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 ATCCD133 + 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.

Original languageEnglish
Pages (from-to)410-423
Number of pages14
JournalJournal of Pharmacology and Experimental Therapeutics
Volume341
Issue number2
DOIs
StatePublished - 1 May 2012

Fingerprint

Dive into the research topics of 'Targeting signal transducer and activator of transcription 3 pathway by cucurbitacin I diminishes self-renewing and radiochemoresistant abilities in thyroid cancer-derived CD133 + cells'. Together they form a unique fingerprint.

Cite this