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.