Oncotarget

Research Papers:

PDHA1 gene knockout in prostate cancer cells results in metabolic reprogramming towards greater glutamine dependence

Yaqing Li, Xiaoran Li, Xiaoli Li, Yali Zhong, Yasai Ji, Dandan Yu, Mingzhi Zhang, Jian-Guo Wen, Hongquan Zhang, Mariusz Adam Goscinski, Jahn M. Nesland and Zhenhe Suo _

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Oncotarget. 2016; 7:53837-53852. https://doi.org/10.18632/oncotarget.10782

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Abstract

Yaqing Li1,2,3, Xiaoran Li2,3, Xiaoli Li1,2, Yali Zhong1, Yasai Ji1, Dandan Yu1,2, Mingzhi Zhang1, Jian-Guo Wen4, Hongquan Zhang5, Mariusz Adam Goscinski6, Jahn M. Nesland2,3, Zhenhe Suo1,2,3

1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

2Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway

3Department of Pathology, The Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway

4Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

5Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Peking University, Beijing, China

6Department of Surgery, the Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Oslo, Norway

Correspondence to:

Zhenhe Suo, email: zhenhes@medisin.uio.no

Keywords: PDHA1 gene knockout, metabolic reprogramming, glutamine dependence, prognosis, GC-MS analysis

Received: April 06, 2016    Accepted: July 10, 2016    Published: July 22, 2016

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.


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