Abstract A30: Oncogenic MCT-1 activation deregulates oxidative metabolism and promotes lung tumor progression and metastasis

Abstract

Abstract Multiple copies in T-cell malignancy 1 (MCT-1) is involved in transcription regulation and translation initiation. We have identified that MCT-1 plays important roles in cell transformation and survival, catastrophic mitosis and genomic instability. Enhanced MCT-1 activity decreases p53 promoter function, protein stability and activity, thereby overexpressing MCT-1 further promotes tumorigenicity in a p53-null background. Enhanced MCT-1 activation induces SHCs (Src homology 2 domain containing transforming proteins) that transmit EGFR signaling to extracellular-regulated kinase (ERK) and AKT pathway. Here, we identify a novel carcinoma metabolism pathway involving MCT-1-YY1-EGFR-MnSOD axis which confers oxidative resistance, changes tumor microenvironments and promotes tumor development. Inhibiting this oncogenic pathway may be a novel clinical intervention approach to prevent tumor progression and metastasis. Aims: Reactive oxygen species (ROS) promote tumor progression and metastasis, but the underlying mechanism remains unclear. We aim to investigate whether the oncogenic pathway enhances the generation of ROS, alters tumor microenvironment and potentiates metastasis. Results: We found that oncogene MCT-1 (multiple copies in T-cell malignancy 1) stimulated intracellular ROS formation and mitochondrial superoxide production in relationship with the deregulation of antioxidants and redox signaling. Enhanced MCT-1 activation induced the YY1-EGFR-MnSOD signaling cascade which prevented cells against oxidative damage and promoted tumor development. Importantly, MCT-1 overexpressing in lung cancer cells promoted tumor angiogenesis and necrosis along with increase of tumor-promoted M2 macrophages and cancer-associated myofibroblasts in stroma, which potentially provided a malignant microenvironment for tumor progression and metastasis. Conversely, restricting ROS generation and targeting YY1 suppressed the MCT-1-EGFR-MnSOD pathway and invasion ability in lung cancer cells. Clinical results confirm that MCT-1 overexpression is link to poor clinical outcomes and associates with hyper-activation of YY1, EGFR and MnSOD in patients with lung cancer. Importantly, MCT-1 protein enrichment is often identified in late stage and lymph node metastasis of lung cancer. Innovation and Conclusion: Our data reveal a previously unrecognized mechanism of the oxidative metabolism involving MCT-1-YY1-EGFR-MnSOD network which alters tumor microenvironments and promotes tumor progression and metastasis. Citation Format: Hong-Yu Tseng, Yen-An Chen, Jayu Jen, Yi-Ching Wang, Hsin-Ling Hsu. Oncogenic MCT-1 activation deregulates oxidative metabolism and promotes lung tumor progression and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A30.