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Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells
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Hilaire C. Lam1, Heng-Jia Liu1, Christian V. Baglini1, Harilaos Filippakis1, Nicola Alesi1, Julie Nijmeh1, Heng Du1, Alicia Llorente Lope1, Katherine A. Cottrill2, Adam Handen2, John M. Asara3, David J. Kwiatkowski1, Issam Ben-Sahra4, William M. Oldham1, Stephen Y. Chan2 and Elizabeth P. Henske1
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
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
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<0.01) and ~75% (p<0.0001), respectively, and combined rapamycin treatment decreased soft agar growth by ~90% (p<0.0001). miR-21 inhibition also increased sensitivity to apoptosis. Through a network biology-driven integration of RNAseq data, we discovered that miR-21 promotes mitochondrial adaptation and homeostasis in Tsc2-deficient cells. miR-21 inhibition reduced mitochondrial polarization and function in Tsc2-deficient cells, with and without co-treatment with rapamycin. Importantly, miR-21 inhibition limited Tsc2-deficient tumor growth in vivo, reducing tumor size by approximately 3-fold (p<0.0001). When combined with rapamcyin, miR-21 inhibition showed even more striking efficacy, both during treatment and after treatment cessation, with a 4-fold increase in median survival following rapamycin cessation (p=0.0008). We conclude that miR-21 promotes mTORC1-driven tumorigenesis via a mechanism that involves the mitochondria, and that miR-21 is a potential therapeutic target for TSC-associated hamartomas and other mTORC1-driven tumors, with the potential for synergistic efficacy when combined with rapalogs.
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