title: PDK4 protein promotes tumorigenesis through activation of cAMP-response element-binding protein (CREB)-Ras homolog enriched in brain (RHEB)-mTORC1 signaling cascade.
abstract: Mechanistic target of rapamycin (mTOR) integrates multiple extracellular and intracellular signals to regulate cell growth and survival. Hyperactivation of mTOR has been observed in various cancers. Regulation of mTOR activity is thus of importance in physiological processes and tumor development. Here, we present pyruvate dehydrogenase kinase 4 (PDK4) as a novel regulator of mTORC1 signaling. mTORC1 activity was augmented with PDK4 overexpression and reduced by PDK4 suppression in various cell lines. Furthermore, PDK4 bound to cAMP-response element-binding protein (CREB) and prevented its degradation. The enhanced CREB consequently transactivated the expression of Ras homolog enriched in brain (RHEB), a direct key activator of mTORC1, independent of AMP-activated protein kinase or tuberous sclerosis complex protein 2. PDK4 potentiated the mTORC1 effectors hypoxia-inducible factor 1α and pyruvate kinase isozymes M2 and promoted aerobic glycolysis (Warburg effect). Knockdown of PDK4 suppressed the tumor development of cancer cells with activated mTORC1. The abundance of PDK4 dictated the responsiveness of cells to the mTOR inhibitor, rapamycin. Combinatory suppression of mTOR and PDK4 exerted synergistic inhibition on cancer cell proliferation. Therefore, PDK4 promotes tumorigenesis through activation of the CREB-RHEB-mTORC1 signaling cascade.
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and the Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and.
authors.forename: Haiyong
authors.initials: H
authors.lastname: Peng
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Jing
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and hbzhang@ibms.pumc.edu.cn hbzhang2006@gmail.com.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000332:Aerobiosis / Q000187:drug effects; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003999:Dichloroacetic Acid / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D046912:Multiprotein Complexes; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D003999:Dichloroacetic Acid; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D011770:Pyruvate Kinase; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; D020559:Monomeric GTP-Binding Proteins
keywords: Cellular Regulation; DNA-Protein Interaction; Mechanistic Target of Rapamycin (mTOR); Pyruvate Dehydrogenase Kinase 4; Ras Homolog Enriched in Brain; Signaling; Tumorigenesis; Warburg Effect; cAMP-response Element-binding Protein (CREB)