Cordycepin Regulates GSK-3β/β-Catenin Signaling in Human Leukemia Cells

被引:39
作者
Ko, Bor-Sheng [1 ,2 ]
Lu, Yi-Jhu [1 ]
Yao, Wen-Ling [1 ,3 ]
Liu, Tzu-An [1 ]
Tzean, Shean-Shong [3 ]
Shen, Tang-Long [3 ]
Liou, Jun-Yang [1 ,4 ]
机构
[1] Natl Hlth Res Inst, Inst Cellular & Syst Med, Zhunan, Taiwan
[2] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan
[3] Natl Taiwan Univ, Dept Plant Pathol & Microbiol, Taipei 10764, Taiwan
[4] China Med Univ, Grad Inst Basic Med Sci, Taichung, Taiwan
关键词
TRADITIONAL CHINESE MEDICINE; ACUTE MYELOID-LEUKEMIA; MOUSE MELANOMA-CELLS; BETA-CATENIN; STEM-CELLS; CARCINOMA CELLS; WNT; EXPRESSION; 3'-DEOXYADENOSINE; METASTASIS;
D O I
10.1371/journal.pone.0076320
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
Background: Leukemia stem cells (LSCs) are a limitless cell source for the initiation and maintenance of leukemia. Activation of the Wnt/beta-catenin pathway is required for the survival and development of LSCs. Therefore, targeting beta-catenin is considered a therapeutic strategy for the treatment of leukemia. The goal of this study was to explore whether cordycepin, an active component of the traditional medicine Cordyceps sinensis, regulates beta-catenin expression in leukemia cells. Methodology and Principal Findings: In this study, we found that cordycepin significantly suppressed cell proliferation in all malignant cancer cells, including U937, K562, A549, HepG2, SK-Hep1 and MCF7 in a dose-dependent manner. However, cordycepin reduced beta-catenin levels in U937, K562 and THP1 leukemia cells and had no effect on other solid cancer cells. In addition, treatment with cordycepin significantly suppressed leukemia colony formation in soft agar assay. Cordycepin enhanced proteasome-dependent degradation and inhibited nuclear translocation of beta-catenin in leukemia cells. Cordycepin-reduced beta-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3 beta, indicating that cordycepin-suppressed beta-catenin stability is mediated by the activation of GSK-3 beta. Furthermore, cordycepin abolished the effect of Wnt3a-induced beta-catenin in leukemia cells. In addition, cordycepin-impaired beta-catenin is regulated by Akt activation but is not significantly influenced by AMPK or mTOR signal pathways. Significance: Our findings show for the first time that codycepin selectively reduces beta-catenin stability in leukemia but not in other solid tumor cells. This suppressive effect is mediated by regulating GSK-3 beta. A synergistic combination of cordycepin with other treatments should be used as a novel strategy to eradicate leukemia via elimination of LSCs.
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页数:7
相关论文
共 41 条
[1]
The traditional Chinese medicine Cordyceps sinensis and its effects on apoptotic homeostasis [J].
Buenz, EJ ;
Bauer, BA ;
Osmundson, TW ;
Motley, TJ .
JOURNAL OF ETHNOPHARMACOLOGY, 2005, 96 (1-2) :19-29
[2]
14-3-3σ Regulates β-Catenin-Mediated Mouse Embryonic Stem Cell Proliferation by Sequestering GSK-3β [J].
Chang, Tzu-Ching ;
Liu, Chia-Chia ;
Hsing, En-Wei ;
Liang, Shu-Man ;
Chi, Ya-Hui ;
Sung, Li-Ying ;
Lin, Shau-Ping ;
Shen, Tang-Long ;
Ko, Bor-Sheng ;
Yen, B. Linju ;
Yet, Shaw-Fang ;
Wu, Kenneth K. ;
Liou, Jun-Yang .
PLOS ONE, 2012, 7 (06)
[3]
RNA-directed agent, cordycepin, induces cell death in multiple myeloma cells [J].
Chen, Lisa S. ;
Stellrecht, Christine M. ;
Gandhi, Varsha .
BRITISH JOURNAL OF HAEMATOLOGY, 2008, 140 (06) :682-691
[4]
Cordycepin Induces Apoptosis of CGTH W-2 Thyroid Carcinoma Cells through the Calcium-Calpain-Caspase 7-PARP Pathway [J].
Chen, Ying ;
Chen, Yung-Chia ;
Lin, Yen-Tung ;
Huang, Shih-Horng ;
Wang, Seu-Mei .
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 2010, 58 (22) :11645-11652
[5]
GSK-3: tricks of the trade for a multi-tasking kinase [J].
Doble, BW ;
Woodgett, JR .
JOURNAL OF CELL SCIENCE, 2003, 116 (07) :1175-1186
[6]
Acute Myeloid Leukemia and the Wnt Pathway [J].
Eaves, Connie J. ;
Humphries, R. Keith .
NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (24) :2326-2327
[7]
Genetic and Pharmacologic Inhibition of β-Catenin Targets Imatinib-Resistant Leukemia Stem Cells in CML [J].
Heidel, Florian H. ;
Bullinger, Lars ;
Feng, Zhaohui ;
Wang, Zhu ;
Neff, Tobias A. ;
Stein, Lauren ;
Kalaitzidis, Demetrios ;
Lane, Steve W. ;
Armstrong, Scott A. .
CELL STEM CELL, 2012, 10 (04) :412-424
[8]
β-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia [J].
Hu, Y. ;
Chen, Y. ;
Douglas, L. ;
Li, S. .
LEUKEMIA, 2009, 23 (01) :109-116
[9]
Cordycepin Induced MA-10 Mouse Leydig Tumor Cell Apoptosis through Caspase-9 Pathway [J].
Jen, Chun-Yi ;
Lin, Chun-Yu ;
Huang, Bu-Miin ;
Leu, Sew-Fen .
EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE, 2011, 2011 :1-11
[10]
Induction of apoptosis by cordycepin via reactive oxygen species generation in human leukemia cells [J].
Jeong, Jin-Woo ;
Jin, Cheng-Yun ;
Park, Cheol ;
Hong, Su Hyun ;
Kim, Gi-Young ;
Jeong, Yong Kee ;
Lee, Jae-Dong ;
Yoo, Young Hyun ;
Choi, Yung Hyun .
TOXICOLOGY IN VITRO, 2011, 25 (04) :817-824