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.

Osteocytic miR21 deficiency improves bone strength independent of sex despite having sex divergent effects on osteocyte viability and bone turnover

“…In cardiac tissue, miR21 has been shown to directly promote mitochondrial cytochrome B translation and reduce reactive oxygen species production . Additionally, miR21 promotes mitochondrial homeostasis and adaptation in mTORc1‐activated cells . Further, miR21 promotes cancer cell‐survival by down‐regulating PTEN and consequently activating the PI3K/AKT/mTOR pathway .…”

miR‑124 targets retinoid�X receptor�α to reduce growth of TSC2‑deficient lymphangioleiomyomatosis

“…Changes in miRNA profiling are implicated in various human diseases such as LAM (18,19). However, whether miRNAs contribute to LAM therapy remains to be elucidated.…”

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“…Indeed, direct measurements showed that the combination of rapamycin and miR-21 inhibition reduced mitochondrial content, mitochondrial membrane potential, as well as, overall mitochondrial function. More excitingly, this combined treatment significantly reduced in vivo growth of xenograft tumors and increased survival in mice by four-fold [7].…”

“…al. tested the hypothesis that miR-21 upregulation might help protect TSC2-deficient cells from the cytotoxic effects of mTORC1 inhibition [7]. Interestingly, the authors found that miR-21 is upregulated in TSC2-deficient cells (characterized by high mTORC1 activity) and further induced upon rapamycin treatment (a potent inhibitor of mTORC1).…”