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

Hilaire C. Lam, Heng Jia Liu, Christian V. Baglini, Harilaos Filippakis, Nicola Alesi, Julie Nijmeh, Heng Du, Alicia Llorente Lope, Katherine A. Cottrill, Adam Handen, John M. Asara, David J. Kwiatkowski, Issam Ben-Sahra, William M. Oldham, Stephen Y. Chan, Elizabeth P. Henske*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)64714-64727
Number of pages14
JournalOncotarget
Volume8
Issue number39
DOIs
StatePublished - Jan 1 2017

Keywords

  • MTORC1
  • MiR-21
  • Mitochondria
  • Rapamycin
  • Tuberous sclerosis complex

ASJC Scopus subject areas

  • Oncology

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    Lam, H. C., Liu, H. J., Baglini, C. V., Filippakis, H., Alesi, N., Nijmeh, J., Du, H., Lope, A. L., Cottrill, K. A., Handen, A., Asara, J. M., Kwiatkowski, D. J., Ben-Sahra, I., Oldham, W. M., Chan, S. Y., & Henske, E. P. (2017). Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells. Oncotarget, 8(39), 64714-64727. https://doi.org/10.18632/oncotarget.19947