期刊
CHILDS NERVOUS SYSTEM
卷 28, 期 3, 页码 363-373出版社
SPRINGER
DOI: 10.1007/s00381-011-1672-x
关键词
Medulloblastoma; Cucurbitacin I; Cancer stem cells; CD133; STAT3; Radioresistance
资金
- National Science Council [NSC-98-3111-B-075-001-MY3]
- Yen-Tjing-Ling Medical Foundation [98/99/100]
- Chi Mei Medical Center [CMYM 9801/9901/100001]
- Taipei City Hospital [98/99/100]
- Cheng-Hsin General Hospital [98/99/100]
CD133 (PROM1) is a potential marker for cancer stem cells (CSCs), including those found in brain tumors. Recently, medulloblastoma (MB)-derived CD133-positive cells were found to have CSC-like properties and were proposed to be important contributors to tumorigenicity, cancer progression, and chemoradioresistance. However, the biomolecular pathways and therapeutic targets specific to MB-derived CSCs remain unresolved. In the present study, we isolated CD133(+) cells from MB cell lines and determined that they showed increased tumorigenicity, radioresistance, and higher expression of both embryonic stem cell-related and drug resistance-related genes compared to CD133(-) cells. Bioinformatics analysis suggested that the STAT3 pathway might be important in MB and CD133(+) cells. To evaluate the effects of inhibiting the STAT3 pathway, MB-derived CD133(+/-) cells were treated with the potent STAT3 inhibitor, cucurbitacin I. Treatment with cucurbitacin I significantly suppressed the CSC-like properties and stemness gene signature of MB-derived CD133(+) cells. Furthermore, cucurbitacin I treatment increased the apoptotic sensitivity of MB-derived CD133(+) cells to radiation and chemotherapeutic drugs. Notably, cucurbitacin I demonstrated synergistic effects with ionizing radiation to inhibit tumorigenicity in MB-CD133(+)-inoculated mice. These results indicate that the STAT3 pathway plays a key role in mediating CSC properties in MB-derived CD133(+) cells. Targeting STAT3 with cucurbitacin I may therefore represent a novel therapeutic approach for treating malignant brain tumors.
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