Dataset Information

ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.

ABSTRACT: Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H₂S) production. This H₂S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H₂S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H₂S levels, or enhancing mechanisms that H₂S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.

SUBMITTER: Statzer C

PROVIDER: S-EPMC8857226 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.

Statzer Cyril C Meng Jin J Venz Richard R Bland Monet M Robida-Stubbs Stacey S Patel Krina K Petrovic Dunja D Emsley Raffaella R Liu Pengpeng P Morantte Ianessa I Haynes Cole C Mair William B WB Longchamp Alban A Filipovic Milos R MR Blackwell T Keith TK Ewald Collin Y CY

Nature communications 20220218 1

Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ...[more]

PMID: 35181679

Similar Datasets

Project description:Hydrogen sulfide (H2S), a gaseous signaling molecule, is associated with the development of various malignancies via modulating various cellular signaling cascades. Published research has established the fact that inhibition of endogenous H2S production or exposure of H2S donors is an effective approach against cancer progression. However, the effect of pharmacological inhibition of endogenous H2S-producing enzymes (cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST)) on the growth of breast cancer (BC) remains unknown. In the present study, DL-propargylglycine (PAG, inhibitor of CSE), aminooxyacetic acid (AOAA, inhibitor of CBS), and L-aspartic acid (L-Asp, inhibitor of 3-MPST) were used to determine the role of endogenous H2S in the growth of BC by in vitro and in vivo experiments. An in silico study was also performed to confirm the results. Corresponding to each enzyme in separate groups, we treated BC cells (MCF-7 and MDA-MB-231) with 10 mM of PAG, AOAA, and L-Asp for 24 h. Findings reveal that the combined dose (PAG + AOAA + L-Asp) group showed exclusive inhibitory effects on BC cells' viability, proliferation, migration, and invasion compared to the control group. Further, treated cells exhibited increased apoptosis and a reduced level of phospho (p)-extracellular signal-regulated protein kinases such as p-AKT, p-PI3K, and p-mTOR. Moreover, the combined group exhibited potent inhibitory effects on the growth of BC xenograft tumors in nude mice, without obvious toxicity. The molecular docking results were consistent with the wet lab experiments and enhanced the reliability of the drugs. In conclusion, our results demonstrate that the inhibition of endogenous H2S production can significantly inhibit the growth of human breast cancer cells via the AKT/PI3K/mTOR pathway and suggest that endogenous H2S may act as a promising therapeutic target in human BC cells. Our study also empowers the rationale to design novel H2S-based anti-tumor drugs to cure BC.

Dataset Information

ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.

Publications

ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets