Mitochondrial pyruvate carrier function is negatively linked to Warburg phenotype in vitro and malignant features in esophageal squamous cell carcinomas

// Yaqing Li 1, 2 , Xiaoran Li 2, 3 , Quancheng Kan 4 , Mingzhi Zhang 1 , Xiaoli Li 1, 2 , Ruiping Xu 5 , Junsheng Wang 5 , Dandan Yu 1, 2 , Mariusz Adam Goscinski 6 , Jian-Guo Wen 7 , Jahn M. Nesland 2, 3 , Zhenhe Suo 1, 2, 3 1 Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China 2 Department of Pathology, the Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Oslo, 0379, Norway 3 Department of Pathology, the Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0379, Norway 4 Department of Clinical Pharmacology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China 5 Department of Oncology, the Anyang Tumor Hospital, Anyang, 455000, Henan Province, China 6 Department of Surgery, the Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Oslo, 0379, Norway 7 Institute of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China Correspondence to: Zhenhe Suo, email: zhenhes@medisin.uio.no 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.