Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells |
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Authors: | Charn-Jung Chang Chih-Hung Chiang Wen-Shin Song Shen-Kou Tsai Lin-Chung Woung Chin-Hong Chang Shaw-Yeu Jeng Ching-Yao Tsai Chuan-Chih Hsu Hung-Fu Lee Chi-Shuan Huang Ming-Chi Yung Jorn-Hon Liu Kai-Hsi Lu |
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Institution: | Department of Pharmacy Practice, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan. |
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Abstract: | Introduction 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. Materials and methods 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. Results 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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