Research Papers:
Pyruvate dehydrogenase expression is negatively associated with cell stemness and worse clinical outcome in prostate cancers
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Abstract
Yali Zhong1,2,3,4, Xiaoli Li1, Yasai Ji1, Xiaoran Li3,4, Yaqing Li1, Dandan Yu1, Yuan Yuan5, Jian Liu6, Huixiang Li7, Mingzhi Zhang1, Zhenyu Ji8, Dandan Fan8, Jianguo Wen9, Mariusz Adam Goscinski10, Long Yuan11, Bin Hao12, Jahn M Nesland3,4, Zhenhe Suo1,3,4
1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
2Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
3Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway
4Department of Pathology, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
5Department of Pathology, Capital Medical University, Beijing, China
6Institute of Health Quarantine, Chinese Academy of Inspection and Quarantine, Beijing, China
7Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
8Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou
9Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Henan, China
10Department of Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
11Department of Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
12Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Correspondence to:
Zhenhe Suo, email: [email protected]
Keywords: PDHA1, glycolysis, stemness, prostate cancer
Received: September 30, 2016 Accepted: December 28, 2016 Published: January 05, 2017
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.
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