title: PDHA1 gene knockout in prostate cancer cells results in metabolic reprogramming towards greater glutamine dependence.
abstract: Alternative pathways of metabolism endowed cancer cells with metabolic stress. Inhibiting the related compensatory pathways might achieve synergistic anticancer results. This study demonstrated that pyruvate dehydrogenase E1α gene knockout (PDHA1 KO) resulted in alterations in tumor cell metabolism by rendering the cells with increased expression of glutaminase1 (GLS1) and glutamate dehydrogenase1 (GLUD1), leading to an increase in glutamine-dependent cell survival. Deprivation of glutamine induced cell growth inhibition, increased reactive oxygen species and decreased ATP production. Pharmacological blockade of the glutaminolysis pathway resulted in massive tumor cells apoptosis and dysfunction of ROS scavenge in the LNCaP PDHA1 KO cells. Further examination of the key glutaminolysis enzymes in human prostate cancer samples also revealed that higher levels of GLS1 and GLUD1 expression were significantly associated with aggressive clinicopathological features and poor clinical outcome. These insights supply evidence that glutaminolysis plays a compensatory role for cell survival upon alternative energy metabolism and targeting the glutamine anaplerosis of energy metabolism via GLS1 and GLUD1 in cancer cells may offer a potential novel therapeutic strategy.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.|Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway.|Department of Pathology, The Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway.|Department of Pathology, The Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.|Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
authors.forename: Yasai
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.|Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway.
authors.forename: Dandan
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Wen
authors.affiliation: Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Peking University, Beijing, China.
authors.forename: Hongquan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Surgery, the Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Mariusz Adam
authors.initials: MA
authors.lastname: Goscinski
authors.affiliation: Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway.|Department of Pathology, The Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway.
authors.forename: Jahn M
authors.initials: JM
authors.lastname: Nesland
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.|Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway.|Department of Pathology, The Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway.
authors.forename: Zhenhe
authors.initials: Z
authors.lastname: Suo
mesh_terms: D000368:Aged; D055786:Gene Knockout Techniques; D005969:Glutamate Dehydrogenase / Q000378:metabolism*; D005972:Glutaminase / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism
chemical_list: D005973:Glutamine; D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit; D005969:Glutamate Dehydrogenase; C561840:GLUD1 protein, human; C579480:GLS protein, human; D005972:Glutaminase
keywords: GC-MS analysis; PDHA1 gene knockout; glutamine dependence; metabolic reprogramming; prognosis