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Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells

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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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Acknowledgments

This study was supported by research grants from the National Science Council (NSC-98-3111-B-075-001-MY3), the Yen-Tjing-Ling Medical Foundation (98/99/100),Chi Mei Medical Center (CMYM 9801/9901/100001), Taipei City Hospital (98/99/100), and Cheng-Hsin General Hospital (98/99/100).

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Authors and Affiliations

  1. Department of Pharmacy Practice, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan

    Charn-Jung Chang

  2. Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan

    Wen-Shin Song, Hung-Fu Lee & Chi-Shuan Huang

  3. Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan

    Shen-Kou Tsai, Jorn-Hon Liu & Kai-Hsi Lu

  4. School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Chih-Hung Chiang, Wen-Shin Song, Shen-Kou Tsai, Lin-Chung Woung, Shaw-Yeu Jeng, Ching-Yao Tsai, Hung-Fu Lee, Chi-Shuan Huang, Ming-Chi Yung, Jorn-Hon Liu & Kai-Hsi Lu

  5. Division of Urology, Department of Surgery, Taipei Veterans General Hospital—Su-Ao/Yuan-Shan Branch, Taipei, Taiwan

    Chih-Hung Chiang & Shaw-Yeu Jeng

  6. Department of Ophthalmology, Taipei City Hospital, Taipei, Taiwan

    Lin-Chung Woung & Ching-Yao Tsai

  7. Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan

    Chin-Hong Chang & Chuan-Chih Hsu

  8. Department of Surgery, Taiwan Adventist Hospital, Taipei, Taiwan

    Ming-Chi Yung

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  1. Charn-Jung Chang
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Correspondence to Ming-Chi Yung or Kai-Hsi Lu.

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Chang, CJ., Chiang, CH., Song, WS. et al. Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells. Childs Nerv Syst 28, 363–373 (2012). https://doi.org/10.1007/s00381-011-1672-x

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