Cucurbitacin I suppressed stem-like property and enhanced radiation-induced apoptosis in head and neck squamous carcinoma-derived CD44 +ALDH1+ cells

Yi Wei Chen, Kuan Hsuan Chen, Pin I. Huang, Yu Chih Chen, Guang-Yuh Chiou, Wen Liang Lo, Ling Ming Tseng, Han Sui Hsu, Kuo Wei Chang, Shih Hwa Chiou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer worldwide. Signal transducers and activators of transcription 3 (STAT3) signaling is reported to promote tumor malignancy and recurrence in HNSCC. Cucurbitacins, triterpenoid derivatives, are strong STAT3 inhibitors with anticancer properties. Recent studies have shown aldehyde dehydrogenase 1 (ALDH1) to be amarker of cancer stemcells (CSC) in HNSCC. The aim of this study was to investigate the therapeutic effect of cucurbitacin I in HNSCC-derived CSCs. Using immunohistochemical analysis, we firstly showed that CD44, ALDH1, and phosphorylated STAT3 (p-STAT3) were higher in high-grade HNSCCs, and that triple positivity for CD44/ALDH1/p-STAT3 indicated a worse prognosis for HNSCC patients. Secondly, CD44+ALDH1+ cells isolated from seven HNSCC patients showed greater tumorigenicity, radioresistance, and high expression of stemness (Bmi-1/Oct-4/Nanog) and epithelial-mesenchymal- transitional (Snail/Twist) genes as p-STAT3 level increased. Furthermore, we found that cucurbitacin I (JSI-124) can effectively inhibit the expression of p-STAT3 and capacities for tumorigenicity, sphere formation, and radioresistance in HNSCC-CD44+ALDH1+. Notably, 150 nmol/L cucurbitacin I effectively blocked STAT3 signaling and downstream survivin and Bcl-2 expression, and it induced apoptosis in HNSCC-CD44+ALDH1+. Moreover, microarray data indicated that 100 nmol/L cucurbitacin I facilitated CD44+ALDH1+ cells to differentiate into CD44 -ALDH1- and enhanced the radiosensitivity of HNSCC-CD44+ALDH1+. Xenotransplant experiments revealed that cucurbitacin I combined with radiotherapy significantly suppressed tumorigenesis and lung metastasis and further improved the survival rate in HNSCC-CD44+ALDH1+-transplanted immunocompromised mice. Taken together, our data show that cucurbitacin I, STAT3 inhibitor, reduces radioresistant, distant-metastatic, and CSC-like properties of HNSCC-CD44 +ALDH1+ cells. The potential of cucurbitacin I as a radiosensitizer should be verified in future anti-CSC therapy.

Original languageEnglish
Pages (from-to)2879-2892
Number of pages14
JournalMolecular Cancer Therapeutics
Volume9
Issue number11
DOIs
StatePublished - 1 Nov 2010

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