Targeting PDK1 with dichloroacetophenone to inhibit acute myeloid leukemia (AML) cell growth
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Lijun Qin1,*, Yun Tian2,3,4,5,*, Zhenlong Yu6,*, Dingbo Shi2,3,4, Jingshu Wang2,3,4, Changlin Zhang2,3,4, Ruoyu Peng7, Xuezhen Chen1, Congcong Liu6, Yiming Chen6, Wenlin Huang2,3,4,8 and Wuguo Deng2,3,4,8
1 Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
2 Sun Yat-sen University Cancer Center, Guangzhou, China
3 State Key Laboratory of Oncology in South China, Guangzhou, China
4 Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
5 Guangzhou Women and Children’s Medical Center, Guangzhou, China
6 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
7 Guangdong Provincial No. 2 People’s Hospital, Guangzhou, China
8 State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China
* These authors have contributed equally to this article
Lijun Qin, email:
Yun Tian, email:
Wuguo Deng, email:
keywords: PDK1, AML, apoptosis, autophagy, BCL-xl
Received: July 10, 2015 Accepted: November 15, 2015 Published: November 22, 2015
Pyruvate dehydrogenase kinase-1 (PDK1), a key metabolic enzyme involved in aerobic glycolysis, is highly expressed in many solid tumors. Small molecule compound DAP (2,2-dichloroacetophenone) is a potent inhibitor of PDK1. Whether targeting PDK1 with DAP can inhibit acute myeloid leukemia (AML) and how it works remains unknown. In this study, we evaluated the effect of inhibition of PDK1 with DAP on cell growth, apoptosis and survival in AML cells and identified the underlying mechanisms. We found that treatment with DAP significantly inhibited cell proliferation, increased apoptosis induction and suppressed autophagy in AML cells in vitro, and inhibited tumor growth in an AML mouse model in vivo. We also showed that inhibition of PDK1 with DAP increased the cleavage of pro-apoptotic proteins (PARP and Caspase 3) and decreased the expression of the anti-apoptotic proteins (BCL-xL and BCL-2) and autophagy regulators (ULK1, Beclin-1 and Atg). In addition, we found that DAP inhibited the PI3K/Akt signaling pathway. Furthermore, we demonstrated that PDK1 interacted with ULK1, BCL-xL and E3 ligase CBL-b in AML cells, and DPA treatment could inhibit the interactions. Collectively, our results indicated that targeting PDK1 with DAP inhibited AML cell growth via multiple signaling pathways and suggest that targeting PDK1 may be a promising therapeutic strategy for AMLs.
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