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Cardamonin induces apoptosis by suppressing STAT3 signaling pathway in glioblastoma stem cells

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Tumor Biology

Abstract

Glioblastoma stem cells (GSCs) are the initiating cells in glioblastoma multiforme (GBM) and contribute to the resistance of GBM to chemotherapy and radiation. In the present study, we investigated the effects of cardamonin (3,4,2,4-tetrahydroxychalcone) on the self-renewal and apoptosis of GSCs, and if its action is associated with signal transducer and activator of transcription 3 (STAT3) pathway. CD133+ GSCs, a kind of GSCs line, was established from human glioblastoma tissues. Cardamonin inhibited the proliferation and induced apoptosis in CD133+ GSCs. The proapoptotic effects of temozolomide (TMZ) were further enhanced by cardamonin in CD133+ GSCs and U87 cells in vitro. For in vivo study, injection of 5 × 105 cells of CD133+ GSCs subcutaneously (s.c.) into nude mice, 100 % of large tumors were developed within 8 weeks in all mice; in contrast, only one out of five mice developed a small tumor when 5 × 105 cells of CD133− GMBs cells were injected. Cardamonin also inhibited STAT3 activation by luciferase assay and suppressed the expression of the downstream genes of STAT3, such as Bcl-XL, Bcl-2, Mcl-1, survivin, and VEGF. Furthermore, cardamonin locked nuclear translocation and dimerization of STAT3 in CD133+ GSCs. Docking analysis confirmed that cardamonin molecule was successfully docked into the active sites of STAT3 with a highly favorable binding energy of −10.78 kcal/mol. The study provides evidence that cardamonin is a novel inhibitor of STAT3 and has the potential to be developed as a new anticancer agent targeting GSCs. This study also reveals that targeting STAT3 signal pathway is an important strategy for the treatment of human GBM.

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Acknowledgments

We are grateful to Dr. Kuan Hu for the technical assistance. This study was supported by the grants from the National Natural Science Foundation of China (No. 41306157 and No. 81273550) and Basic research projects of Qingdao Science and Technology plan (12-1-4-8-(4)-jch).

Conflicts of interest

The authors have no conflicts of interest to declare.

Contributions

Ning Wu, Shousong Cao, Dayong Shi, and Xiukun Lin designed the research study and wrote the manuscript;

Ning Wu, Jia Liu, and Xiangzhong Zhao performed the experiments;

Jia Liu and Lijun Wang analyzed the data;

Zhiyong Yan and Bo Jiang contribute to prepare the regents and materials.

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    Authors and Affiliations

    1. Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China

      Ning Wu, Bo Jiang, Lijun Wang & Dayong Shi

    2. College of Medicine, Qingdao University, Qingdao, 266021, China

      Jia Liu

    3. Qingdao Medical University Affiliated Hospital, Qingdao, 266070, China

      Xiangzhong Zhao & Zhiyong Yan

    4. Chifeng Saliont Pharmaceutical Co., Ltd, Chifeng, Inner Mongolia Autonomous Region, China

      Shousong Cao

    5. Department of Pharmacology, Capital Medical University, Beijing, 100069, China

      Xiukun Lin

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    1. Ning Wu
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    Correspondence to Dayong Shi or Xiukun Lin.

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    Highlights

    1. Cadamonin, a promising anticancer agent, is proposed for treatment of glioblastoma by attacking its stem cells.

    2. Cardamonin inhibits cell renewal and induces apoptosis by suppressing JAK/STAT pathway in the glioblastoma stem cell.

    3. Cardamonin molecule is predicted to be docked into the active site of STAT3 and blocking the activation of STAT3.

    4. Stat3 is a promising target for glioblastoma therapy.

    Ning Wu and Jia Liu contributed equally to this work.

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    Wu, N., Liu, J., Zhao, X. et al. Cardamonin induces apoptosis by suppressing STAT3 signaling pathway in glioblastoma stem cells. Tumor Biol. 36, 9667–9676 (2015). https://doi.org/10.1007/s13277-015-3673-y

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    • DOI: https://doi.org/10.1007/s13277-015-3673-y

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