Oncotarget

Research Papers:

Butein inhibits cell proliferation and induces cell cycle arrest in acute lymphoblastic leukemia via FOXO3a/p27kip1 pathway

Yan-Lai Tang _, Li-Bin Huang, Wen-Hao Lin, Li-Na Wang, Yun Tian, Dingbo Shi, Jingshu Wang, Ge Qin, Anchuan Li, Yan-Ni Liang, Huan-Juan Zhou, Zhi-Yong Ke, Wenlin Huang, Wuguo Deng and Xue-Qun Luo

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Oncotarget. 2016; 7:18651-18664. https://doi.org/10.18632/oncotarget.7624

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Abstract

Yan-Lai Tang1,*, Li-Bin Huang1,*, Wen-Hao Lin1,*, Li-Na Wang1, Yun Tian2, Dingbo Shi2, Jingshu Wang2, Ge Qin2, Anchuan Li3, Yan-Ni Liang1, Huan-Juan Zhou1, Zhi-Yong Ke1, Wenlin Huang2,4, Wuguo Deng2,4, Xue-Qun Luo1

1Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

2Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

3Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, China

4State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China

*These authors have contributed equally to this work

Correspondence to:

Xue-Qun Luo, e-mail: l-xuequn@126.com

Wuguo Deng, e-mail: dengwg@sysucc.org.cn

Keywords: butein, acute lymphoblastic leukemia, FOXO3a, p27kip1

Received: November 22, 2015    Accepted: February 14, 2016    Published: February 23, 2016

ABSTRACT

Acute lymphoblastic leukemia (ALL) is a common hematological malignancy characterized by the uncontrolled proliferation of leukemia cells in children. Discovering and developing effective chemotherapeutic drugs are needed for ALL. In this study, we investigated the anti-leukemic activity of butein and its action mechanisms in ALL. Butein was found to significantly suppress the cellular proliferation of ALL cell lines and primary ALL blasts in a dose-dependent manner. It also induced cell cycle arrest by decreasing the expression of cyclin E and CDK2. We also found that butein promoted nuclear Forkhead Class box O3a (FOXO3a) localization, enhanced the binding of FOXO3a on the p27kip1 gene promoter and then increased the expression of p27kip1. Moreover, we showed that FOXO3a knockdown significantly decreased the proliferation inhibition by butein, whereas overexpression of FOXO3a enhanced the butein-mediated proliferation inhibition. However, overexpression of FOXO3a mutation (C-terminally truncated FOXO3a DNA-binding domain) decreased the proliferation inhibition by butein through decreasing the expression of p27kip1. Our results therefore demonstrate the therapeutic potential of butein for ALL via FOXO3a/p27kip1 pathway.


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