Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells

// Hilaire C. Lam 1 , Heng-Jia Liu 1 , Christian V. Baglini 1 , Harilaos Filippakis 1 , Nicola Alesi 1 , Julie Nijmeh 1 , Heng Du 1 , Alicia Llorente Lope 1 , Katherine A. Cottrill 2 , Adam Handen 2 , John M. Asara 3 , David J. Kwiatkowski 1 , Issam Ben-Sahra 4 , William M. Oldham 1 , Stephen Y. Chan 2 and Elizabeth P. Henske 1 1 Department of Medicine, Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA 2 Department of Medicine, Division of Cardiology, Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA 3 Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 4 Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA Correspondence to: Elizabeth P. Henske, email: // Keywords : tuberous sclerosis complex, mTORC1, rapamycin, miR-21, mitochondria Received : June 20, 2017 Accepted : June 25, 2017 Published : August 04, 2017 Abstract mTORC1 hyperactivation drives the multi-organ hamartomatous disease tuberous sclerosis complex (TSC). Rapamycin inhibits mTORC1, inducing partial tumor responses; however, the tumors regrow following treatment cessation. We discovered that the oncogenic miRNA, miR-21, is increased in Tsc2-deficient cells and, surprisingly, further increased by rapamycin. To determine the impact of miR-21 in TSC, we inhibited miR-21 in vitro . miR-21 inhibition significantly repressed the tumorigenic potential of Tsc2-deficient cells and increased apoptosis sensitivity. Tsc2-deficient cells’ clonogenic and anchorage independent growth were reduced by ~50% ( p