Abstract 790: STAT3 control of mitochondrial RNA stability and translation is a vulnerability in tumors

Abstract

Abstract Signal Transducer and Activator of Transcription (STAT)3 is a critical signalling molecule and transcription factor activated downstream of cytokines and growth factors to regulate immune responses, metabolism, proliferation and cell death. Whilst the activity of STAT3 is crucial for sustenance of life, aberrant activity is observed in around 50% of all human cancers. However, recent evidence has shown non-transcriptional activities of STAT3 that are critical for tumor growth. Mitochondria are the central powerhouse of the cell and provide the biomolecules required for rapid cell proliferation. Recently we showed that a pool of STAT3 resides in mitochondria and enhances the activity of complex I, II and V of the electron transport chain (ETC) driving Ras-dependent malignant transformation. Whilst STAT3 can physically interact with complex I, its low abundance compared to complex I suggests that a direct protein-protein interaction is unlikely to dictate metabolic activity of the ETC.To elucidate mitochondrial activity of STAT3, we isolated STAT3 from mitochondrial fractions of Ras-driven lung adenocarcinoma (A549 cell line) and identified its interactome using mass spectrometry. We show that STAT3 forms a stable 400 kDa complex with the LRPPRC/SLIRP proteins which are key regulators of mitochondrial mRNA stability and translation. STAT3 loss significantly reduced steady state levels of polyadenylated mitochondrial RNA which is due to instability of the polyadenylated transcripts but not due to changes in mitochondrial DNA copy number, differences in mitochondrial transcription kinetics or mitochondrial RNA processing. Furthermore, in the absence of STAT3 there is defective delivery of these transcripts to the mitochondrial ribosomes resulting in delayed mitochondrial translational kinetics. We propose that the ability of STAT3 to regulate mitochondrial transcription and translation is the fundamental mechanism by which a small pool of STAT3 can regulate highly abundant key component proteins of the ETC. Importantly, this activity is required for tumor formation, but is dispensable in normal tissues which makes this activity of STAT3 an attractive therapeutic target that will diminish tumor growth whilst preserving the critical nuclear functions of STAT3. Citation Format: Chamira D. Fernando, Daniel J. Garama, Daniel J. Gough. STAT3 control of mitochondrial RNA stability and translation is a vulnerability in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 790.