title: Pyruvate dehydrogenase expression is negatively associated with cell stemness and worse clinical outcome in prostate cancers.
abstract: Cells generate adenosine-5'-triphosphate (ATP), the major currency for energy-consuming reactions, through mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. One of the remarkable features of cancer cells is aerobic glycolysis, also known as the "Warburg Effect", in which cancer cells rely preferentially on glycolysis instead of mitochondrial OXPHOS as the main energy source even in the presence of high oxygen tension. One of the main players in controlling OXPHOS is the mitochondrial gatekeeperpyruvate dehydrogenase complex (PDHc) and its major subunit is E1α (PDHA1). To further analyze the function of PDHA1 in cancer cells, it was knock out (KO) in the human prostate cancer cell line LnCap and a stable KO cell line was established. We demonstrated that PDHA1 gene KO significantly decreased mitochondrial OXPHOS and promoted anaerobic glycolysis, accompanied with higher stemness phenotype including resistance to chemotherapy, enhanced migration ability and increased expression of cancer stem cell markers. We also examined PDHA1 protein expression in prostate cancer tissues by immunohistochemistry and observed that reduced PDHA1 protein expression in clinical prostate carcinomas was significantly correlated with poor prognosis. Collectively, our results show that negative PDHA1 gene expressionis associated with significantly higher cell stemness in prostate cancer cells and reduced protein expression of this gene is associated with shorter clinical outcome in prostate cancers.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.|Department of Gastroenterology, The Second 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, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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: 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: Yasai
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway.|Department of Pathology, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 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.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Pathology, Capital Medical University, Beijing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Institute of Health Quarantine, Chinese Academy of Inspection and Quarantine, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
authors.forename: Huixiang
authors.initials: H
authors.lastname: Li
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: Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ji
authors.affiliation: Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou.
authors.forename: Dandan
authors.initials: D
authors.lastname: Fan
authors.affiliation: Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Henan, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Mariusz Adam
authors.initials: MA
authors.lastname: Goscinski
authors.affiliation: Department of Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Long
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hao
authors.affiliation: Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway.|Department of Pathology, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 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, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Zhenhe
authors.initials: Z
authors.lastname: Suo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism*
chemical_list: D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit
keywords: PDHA1; glycolysis; prostate cancer; stemness