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

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

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Title: Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells
Author: Lam, Hilaire C.; Liu, Heng-Jia; Baglini, Christian V.; Filippakis, Harilaos; Alesi, Nicola; Nijmeh, Julie; Du, Heng; Lope, Alicia Llorente; Cottrill, Katherine A.; Handen, Adam; Asara, John M.; Kwiatkowski, David J.; Ben-Sahra, Issam; Oldham, William M.; Chan, Stephen Y.; Henske, Elizabeth P.

Note: Order does not necessarily reflect citation order of authors.

Citation: Lam, H. C., H. Liu, C. V. Baglini, H. Filippakis, N. Alesi, J. Nijmeh, H. Du, et al. 2017. “Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells.” Oncotarget 8 (39): 64714-64727. doi:10.18632/oncotarget.19947. http://dx.doi.org/10.18632/oncotarget.19947.
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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<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.
Published Version: doi:10.18632/oncotarget.19947
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630288/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492142
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