Research Papers:
Mitochondrial pyruvate carrier function is negatively linked to Warburg phenotype in vitro and malignant features in esophageal squamous cell carcinomas
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Abstract
Yaqing Li1,2, Xiaoran Li2,3, Quancheng Kan4, Mingzhi Zhang1, Xiaoli Li1,2, Ruiping Xu5, Junsheng Wang5, Dandan Yu1,2, Mariusz Adam Goscinski6, Jian-Guo Wen7, Jahn M. Nesland2,3, Zhenhe Suo1,2,3
1Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China
2Department of Pathology, the Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Oslo, 0379, Norway
3Department of Pathology, the Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0379, Norway
4Department of Clinical Pharmacology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China
5Department of Oncology, the Anyang Tumor Hospital, Anyang, 455000, Henan Province, China
6Department of Surgery, the Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Oslo, 0379, Norway
7Institute of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China
Correspondence to:
Zhenhe Suo, email: [email protected]
Keywords: UK5099, Warburg effect, metabolic reprogramming, bioenergetic profiles, HIF-1α
Received: September 02, 2016 Accepted: October 28, 2016 Published: November 30, 2016
ABSTRACT
Aerobic glycolysis is one of the emerging hallmarks of cancer cells. In this study, we investigated the relationship between blocking mitochondrial pyruvate carrier (MPC) with MPC blocker UK5099 and the metabolic alteration as well as aggressive features of esophageal squamous carcinoma. It was found that blocking pyruvate transportation into mitochondria attenuated mitochondrial oxidative phosphorylation (OXPHOS) and triggered aerobic glycolysis, a feature of Warburg effect. In addition, the HIF-1α expression and ROS production were also activated upon UK5099 application. It was further revealed that the UK5099-treated cells became significantly more resistant to chemotherapy and radiotherapy, and the UK5099-treated tumor cells also exhibited stronger invasive capacity compared to the parental cells. In contrast to esophageal squamous epithelium cells, decreased MPC protein expression was observed in a series of 157 human squamous cell carcinomas, and low/negative MPC1 expression predicted an unfavorable clinical outcome. All these results together revealed the potential connection of altered MPC expression/activity with the Warburg metabolic reprogramming and tumor aggressiveness in cell lines and clinical samples. Collectively, our findings highlighted a therapeutic strategy targeting Warburg reprogramming of human esophageal squamous cell carcinomas.
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