Details

Autor(en) / Beteiligte

• Qin, Lijun
• Tian, Yun
• Yu, Zhenlong
• Shi, Dingbo
• Wang, Jingshu
• Zhang, Changlin
• Peng, Ruoyu
• Chen, Xuezhen
• Liu, Congcong
• Chen, Yiming
• Huang, Wenlin
• Deng, Wuguo

Titel

Targeting PDK1 with dichloroacetophenone to inhibit acute myeloid leukemia (AML) cell growth

Ist Teil von

• Oncotarget, 2016-01, Vol.7 (2), p.1395-1407

Ort / Verlag

United States: Impact Journals LLC

Erscheinungsjahr

2016

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.