Downregulation of TFAM inhibits the tumorigenesis of non-small cell lung cancer by activating ROS-mediated JNK/p38MAPK signaling and reducing cellular bioenergetics

// Deyao Xie 1, 2, * , Xiaoyi Wu 2, * , Linhua Lan 2, * , Fugeng Shangguan 2 , Xiaoming Lin 1 , Fuhong Chen 2 , Shan Xu 2, 3 , Ya Zhang 2 , Zilei Chen 2 , Kate Huang 4 , Rongrong Wang 4 , Lu Wang 2 , Xiaoxiao Song 5 , Yongzhang Liu 2 , Bin Lu 2 1 Department of Cardiothoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China 2 Protein Quality Control and Diseases Laboratory, Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China 3 Huzhou Health School, Huzhou, Zhejiang 313100, P.R. China 4 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China 5 Department of Otolaryngology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China * These authors contributed equally to this work Correspondence to: Bin Lu, e-mail: lubmito@wmu.edu.cn Yongzhang Liu, e-mail: lyz@wmu.edu.cn Keywords: mitochondria, TFAM, non-small cell lung cancer, chemosensitivity, cellular bioenergetics Received: June 04, 2015      Accepted: January 07, 2016      Published: January 25, 2016 ABSTRACT Mitochondrial transcription factor A (TFAM) is essential for the replication, transcription and maintenance of mitochondrial DNA (mtDNA). The role of TFAM in non-small cell lung cancer (NSCLC) remains largely unknown. Herein, we report that downregulation of TFAM in NSCLC cells resulted in cell cycle arrest at G1 phase and significantly blocked NSCLC cell growth and migration through the activation of reactive oxygen species (ROS)-induced c-Jun amino-terminal kinase(JNK)/p38 MAPK signaling and decreased cellular bioenergetics. We further found that TFAM downregulation in NSCLC cells led to increased apoptotic cell death and enhanced the sensitivity of NSCLC cells to cisplatin. Tissue microarray (TMA) data showed that elevated expression of TFAM was related to the histological grade and TNM stage of NSCLC patients. We also demonstrated that TFAM is an independent prognostic factor for overall survival of NSCLC patients. Taken together, our findings suggest that TFAM could serve as a potential diagnostic biomarker and molecular target for the treatment of NSCLC, as well as for prediction of the effectiveness of chemotherapy.