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

doi:10.18632/oncotarget.19947

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

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

17 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 language	English (US)
Pages (from-to)	64714-64727
Number of pages	14
Journal	Oncotarget
Volume	8
Issue number	39
DOIs	https://doi.org/10.18632/oncotarget.19947
State	Published - 2017

Funding

We would like to thank Mary Piper and Lorena Pantano of the Harvard Chan Bioinformatics Core for assistance with RNAseq processing and analysis. Bioinformatics analysis was provided by the Harvard Chan Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, MA. The project described was conducted with the support of Harvard Catalyst | The Harvard Clinical and Translational Science Center (NIH award #UL1 RR 025758 and financial contributions from participating institutions). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.This work was supported by the Engles Program in TSC and LAM Research, R01 DK096556 (E.P. Henske), R01 HL124021, R01 HL122596 (S.Y. Chan), 5P01CA120964, 5P30CA006516 (J.M. Asara) and a postdoctoral Fellowship from The LAM Foundation (H.C. Lam).

Keywords

MTORC1
MiR-21
Mitochondria
Rapamycin
Tuberous sclerosis complex

ASJC Scopus subject areas

Oncology

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10.18632/oncotarget.19947

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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

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title = "Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells",

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.",

keywords = "MTORC1, MiR-21, Mitochondria, Rapamycin, Tuberous sclerosis complex",

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

note = "Publisher Copyright: {\textcopyright} Lam et al.",

year = "2017",

doi = "10.18632/oncotarget.19947",

language = "English (US)",

volume = "8",

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Lam, HC, Liu, HJ, Baglini, CV, Filippakis, H, Alesi, N, Nijmeh, J, Du, H, Lope, AL, Cottrill, KA, Handen, A, Asara, JM, Kwiatkowski, DJ, Ben-Sahra, I, Oldham, WM, Chan, SY & Henske, EP 2017, 'Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells', Oncotarget, vol. 8, no. 39, pp. 64714-64727. https://doi.org/10.18632/oncotarget.19947

TY - JOUR

T1 - Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells

AU - Lam, Hilaire C.

AU - Liu, Heng Jia

AU - Baglini, Christian V.

AU - Filippakis, Harilaos

AU - Alesi, Nicola

AU - Nijmeh, Julie

AU - Du, Heng

AU - Lope, Alicia Llorente

AU - Cottrill, Katherine A.

AU - Handen, Adam

AU - Asara, John M.

AU - Kwiatkowski, David J.

AU - Ben-Sahra, Issam

AU - Oldham, William M.

AU - Chan, Stephen Y.

AU - Henske, Elizabeth P.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - MTORC1

KW - MiR-21

KW - Mitochondria

KW - Rapamycin

KW - Tuberous sclerosis complex

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AN - SCOPUS:85030119506

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

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