title: Targeting PDK1 with dichloroacetophenone to inhibit acute myeloid leukemia (AML) cell growth.
abstract: 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.
authors.affiliation: Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Qin
authors.affiliation: Sun Yat-sen University Cancer Center, Guangzhou, China.|State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|Guangzhou Women and Children's Medical Center, Guangzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Sun Yat-sen University Cancer Center, Guangzhou, China.|State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Dingbo
authors.initials: D
authors.lastname: Shi
authors.affiliation: Sun Yat-sen University Cancer Center, Guangzhou, China.|State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Jingshu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Sun Yat-sen University Cancer Center, Guangzhou, China.|State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial No. 2 People's Hospital, Guangzhou, China.
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Peng
authors.affiliation: Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xuezhen
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Congcong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Sun Yat-sen University Cancer Center, Guangzhou, China.|State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Sun Yat-sen University Cancer Center, Guangzhou, China.|State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008812:Mice, Hairless; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C000612262:2,2-dichloroacetophenone; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: AML; BCL-xl; PDK1; apoptosis; autophagy