Cucurbitacin I suppressed stem-like property and enhanced radiation-induced apoptosis in head and neck squamous carcinoma--derived CD44(+)ALDH1(+) cells.
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 a marker of cancer stem cells (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.
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Yi-Wei
YW
Chen
Kuan-Hsuan
KH
Chen
Pin-I
PI
Huang
Yu-Chih
YC
Chen
Guang-Yu
GY
Chiou
Wen-Liang
WL
Lo
Ling-Ming
LM
Tseng
Han-Sui
HS
Hsu
Kuo-Wei
KW
Chang
Shih-Hwa
SH
Chiou
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002277:Carcinoma / Q000473:pathology / Q000532:radiotherapy; D002294:Carcinoma, Squamous Cell; D015536:Down-Regulation / Q000187:drug effects; D005720:Gamma Rays / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018307:Neoplasms, Squamous Cell / Q000473:pathology / Q000532:radiotherapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D050697:Retinal Dehydrogenase; D000077195:Squamous Cell Carcinoma of Head and Neck; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018960:Hyaluronan Receptors; D007527:Isoenzymes; D011838:Radiation-Sensitizing Agents; D014315:Triterpenes; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; C038106:cucurbitacin I