MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation

Abstract

The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-κB transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.

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Figure 1: Rapamycin decreases the SASP through MTORC1.
Figure 2: SASP production is MTOR dependent.
Figure 3: Rapamycin suppresses NF-κB transcriptional activity.
Figure 4: Rapamycin suppresses IL1A signalling.
Figure 5: Rapamycin inhibits IL1A translation.
Figure 6: Rapamycin does not reverse cellular senescence.
Figure 7: Sustained effect of rapamycin on the SASP.
Figure 8: Rapamycin suppresses the tumour-promoting activity of senescent cells.

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Acknowledgements

We thank A. Rogers, B. Kennedy, G. Lithgow, S. Melov and members of the Campisi laboratory (Buck Institute) for comments and discussions, I. Coleman for assistance with figure preparation and data analysis, and R. Strong (U Texas Health Science Center) for providing the rapamycin encapsulated chow. This work was supported by grants from the National Institutes of Health (NIH) AG045288 to R.-M.L., Hillblom Medical Foundation (CP), NIH T32 training grant AG000266-16 to K.A.W.-E., NIH grants CA143858, CA155679 and CA071468 to C.C.B., NIH grants AG032113 and AG025901 to P.K., DOD-PCRP grant PC111703 and National Natural Science Foundation of China 81472709 to Y.S., NIH grants CA164188, CA165573 and CA097186 and the Prostate Cancer Foundation to P.S.N., and NIH grants AG09909 and AG017242 to J.C. and AG041122 to J.C. and Y.I.

Author information

R.-M.L., Y.S., A.V.O., C.K.P., A.F., L.Z., S.C.C., A.R.D., K.A.W.-E., S.L., C.L., M.D. and P.L. acquired and interpreted the data. M.J. analysed rapamycin concentrations. G.B.H. and Y.I. provided pathological assessment. R.-M.L., Y.S., C.C.B., P.-Y.D., P.K., P.S.N. and J.C. designed experiments and interpreted data. R.-M.L., Y.S., P.-Y.D., P.K., P.S.N. and J.C. wrote the paper.

Correspondence to Judith Campisi.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 4 Rapamycin suppresses the SASP in multiple cell strains and lines.

(A) IL-6 secretion by IR-induced senescent cells, normalized to replicatively senescent IMR-90 normal fetal lung human fibroblasts. Shown are WI-38 normal fetal lung fibroblasts, MCF10-A and 184A1 immortal human breast epithelial cells and PSC27 normal adult prostate fibroblasts, treated with either DMSO (blue bars) or rapamycin (red bars). (B) We treated non-senescent (NS) HCA2 cells with rapamycin for 6 days, collected CM and analyzed IL-6 by ELISA. IL-6 secretion by irradiated senescent cells (Sen (IR)) is shown for comparison. (C) Immunofluorescence staining for 53BP1 was compared between NS and senescent (Sen IR) cells treated with DMSO or rapamycin (one representative image is shown). (D) We determined the number of foci in NS or senescent (Sen IR) cells treated with DMSO or rapamycin. With the exception of 184A1 experiment which was performed once, for panels A, B and D, shown is one representative of two or more independent experiments, each with triplicate samples. Raw data could be found in Supplementary Table 4.

Supplementary Figure 5 The SASP is MTOR dependent.

(A) HCA2 cells were infected with lentiviruses expressing shRNAs against GFP (shGFP; control) or one of three different shRNAs against raptor. Raptor transcript levels were measured and are shown relative the level in cells expressing shGFP. (B) HCA2 cells were infected with lentiviruses expressing shGFP (control) or one of three different shRNA against MTOR. The relative transcript level of MTOR was measured. (C) Normal HCA2 human foreskin fibroblasts, non-senescent (NS) or induced to senesce by IR, were treated with DMSO (control) or the indicated concentrations of the MTOR kinase inhibitor PP242. 7 days later, CM was collected and analyzed for IL-6 by ELISA. Values were normalized to the senescent cell level. For all panels, shown is one representative of two independent experiments, each with triplicate samples. Raw data could be found in Supplementary Table 4.

Supplementary Figure 6 Rapamycin reduces SASP transcript levels and NF-kB activity in senescent prostate fibroblasts.

(A) Transcript levels of indicated SASP factors were quantified by qRT-PCR in NS and Sen (IR) PSC27 fibroblasts with or without treatment with rapamycin for 7 days. (B) NF-κB activity was measured after treatment with rapamycin for 7 days using a reporter assay. For all panels, shown is one representative of three independent experiments, each with triplicate samples. Raw data could be found in Supplementary Table 4.

Supplementary Figure 7 FACS analysis of cell surface IL-1α.

(A) Flow cytometry for cell surface IL-1α was performed using NS or senescent (IR) HCA2 cells expressing shRNAs against GFP or raptor and treated with DMSO or rapamycin and a FITC-tagged antibody. Slope of a trend-line of fluorescence over forward scattering (FSC) was determined to discriminate fluorescence intensity from the effect of cell size (shown is the result of one of two independent experiments, 10,000 cells were counter before gating). (B) HCA2 cells were infected with a lentivirus expressing shRNA against IL-1 α and the relative IL-1 α mRNA level was measured. Shown is one representative of two independent experiments, each with triplicate samples. Raw data could be found in Supplementary Table 4.

Supplementary Figure 8 Translation status of various transcripts after rapamycin treatment.

(A) After IR, senescent (Sen (IR)) HCA2 cells were treated for 1 day with rapamycin or DMSO followed by 1 day in serum-free media, after which cells were harvested and mRNA collected for polysome profiling. qPCR was performed on each fraction for IL1A, IL1B, IL6, IL8, IL3, IL5, TIMP1, CCL13 and TUBA1A mRNA (one representative experiment is shown). Fractions 1–7: Free RNA; 8–12: 40-60S; 13–20: polysomes. (B) NS or senescent (Sen (IR)) HCA2 cells were cultured for 7 days and then treated with DMSO or rapamycin for 4 h, after which cells were harvested and mRNA collected for polysome profiling. qPCR was performed on each fraction for IL1A, TUBA1A, IL6, and EEF2 mRNA (one representative experiment is shown). Fractions 1–4: Free RNA; 5–6: 40-60S; 7–11: polysomes. Right panel: polysome profiles used to determine the translated fractions. All polysome profile data are based on at least two independent replicates; representative polysome traces are shown. Raw data could be found in Supplementary Table 4.

Supplementary Figure 9 MTORC1 inhibition does not reverse the senescence growth arrest.

(A) Effect of rapamycin on the number of senescent cells with detectable senescence-associated β-gal (SA-β-gal) activity. (B) Proliferative potential of PSC27 fibroblasts was measured under the indicated culture conditions. (C) PSC27 cells, NS or made senescent by IR and treated with DMSO or rapamycin for 6 days, were pulsed with BrdU for 24 h and the fraction that incorporated BrdU was determined by fluorescence microscopy. (D) SA-β-gal expression was determined for the cell populations described in Fig. 1 (one representative experiment is shown). (E) Clonogenic assays were performed on HCA2 cells to compare the effects of rapamycin and DMSO on NS cells or cells irradiated at 6, 8 or 10 Gy (one representative experiment is shown). (F) BJ and HCA2 human fibroblasts were irradiated at 5 or 10 Gy and clonogenic assays performed in the presence of DMSO or rapamycin (one representative experiment is shown). For panels A, B and C, shown is one representative of three independent experiments, each with triplicate cell culture samples. For panel D, E and F, shown is one clonogenic assay experiment replicated once. Raw data could be found in Supplementary Table 4.

Supplementary Figure 10 Model for SASP suppression by rapamycin.

(1) Senescence signals activate IL-1α transcription; (2) IL-1α translation is MTOR-dependent and sensitive to rapamycin; (3) IL-1α at the plasma membrane binds the IL1R; (4) IL1R occupancy activates IL1R signaling; (5) IL1R signaling releases IκB, allowing NF-κB translocation to the nucleus, where it activates the transcription of genes encoding SASP factors; (6) SASP factors are transcribed, translated and secreted.

Supplementary Figure 11 Rapamycin suppresses tumour cell growth.

(A) Experimental timeline corresponding to Fig. 8a–c, e. (B) Experimental timeline corresponding to Fig. 8d. (C) PC3 prostate tumour cells were implanted subcutaneously with or without PSC27 prostate fibroblasts, and tumour sizes were measured every 2 weeks. PC3 cells were either exposed to DMSO or rapamycin ex vivo before implantation. PSC27 cells were exposed to ionizing radiation (IR), rapamycin (Rapa) or both ex vivo before implantation (n = 8 per type of treatment). (D) Timeline corresponding to the cell culture experiment presented in Fig. 8f. (E) Timeline corresponding to the in vivo experiment presented in Fig. 8f. Scheduled timing of mitoxantrone given as 3 doses 2 weeks apart, and rapamycin given every 2 days, to SCID mice over the course of an 8 week regimen. The mice were engrafted with PC3 cells alone, or combined with either PSC27-NS (control fibroblasts, without pre-treatment) or PSC27-Sen (IR) (fibroblasts pretreated with IR in culture). At the end of the treatment period, tumours were excised and volumes were determined, with 8-10 mice used per treatment arm. (F) PC3 prostate tumour cells were implanted subcutaneously with or without PSC27 prostate fibroblasts. After 2 weeks of tumour growth, mice were treated with vehicle (control), rapamycin (Rapa) and/or mitoxantrone (MIT). Tumour sizes were measured every 2 weeks (n = 10 per type of treatment). (G) (1) Tumour cells (orange) are surrounded by stromal cells (grey); (2) Treatment with DNA-damaging chemotherapy induces senescence in the stroma (blue cell). The SASP (red arrows) from these senescent cells fuels the proliferation of the remaining tumour cells; (3) Rapamycin reduces the intensity of the SASPs induced by chemotherapy, and tumour cell proliferation is decreased.

Supplementary Table 1 shRNA list.
Supplementary Table 2 Antibodies used for western blotting.
Supplementary Table 3 Primers and probes list.

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Laberge, R., Sun, Y., Orjalo, A. et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 17, 1049–1061 (2015). https://doi.org/10.1038/ncb3195

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