ArticleOncotarget2017
Inhibition of p70 S6 kinase (S6K1) activity by A77 1726, the active metabolite of leflunomide, induces autophagy through TAK1-mediated AMPK and JNK activation.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- The Role of S6K1 in Aging and Alzheimer's Disease: Mechanistic Insights and Therapeutic Potential.International journal of molecular sciences · 2025Review
- Review
- Evaluation of the Combination of Metformin and Rapamycin in an MPPAdvances in pharmacological and pharmaceutical sciences · 2023Article
- Porcine epidemic diarrhoea virus (PEDV) infection activates AMPK and JNK through TAK1 to induce autophagy and enhance virus replication.Virulence · 2022Article
- Inhibition of the sonic hedgehog pathway activates TGF-β-activated kinase (TAK1) to induce autophagy and suppress apoptosis in thyroid tumor cells.Cell death & disease · 2021Article
- Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review.International immunopharmacology · 2021Review
- Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targeting JAK and Src tyrosine kinases.Virology · 2020Article
- Dietary Mitophagy Enhancer: A Strategy for Healthy Brain Aging?Antioxidants (Basel, Switzerland) · 2020Review
- Current Insights in Genetics of Sarcoidosis: Functional and Clinical Impacts.Journal of clinical medicine · 2020Review
- Computer-aided discovery of phenylpyrazole based amides as potent S6K1 inhibitors.RSC medicinal chemistry · 2020Article
- Rapamycin enhanced the antitumor effects of doxorubicin in myelogenous leukemia K562 cells by downregulating the mTOR/p70S6K pathway.Oncology letters · 2019Article
- AMPK-Targeted Effector Networks in Mycobacterial Infection.Frontiers in microbiology · 2019Review
- Gingerenone A Sensitizes the Insulin Receptor and Increases Glucose Uptake by Inhibiting the Activity of p70 S6 Kinase.Molecular nutrition & food research · 2018Article
- Is TAK1 a Direct Upstream Kinase of AMPK?International journal of molecular sciences · 2018Review
- Activation of TGF-β-activated kinase 1 (TAK1) restricts Salmonella Typhimurium growth by inducing AMPK activation and autophagy.Cell death & disease · 2018Article
- Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates.Cell death & disease · 2018Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
mTOR activation suppresses autophagy by phosphorylating ULK1 at S757 and suppressing its enzymatic activity. Here we report that feedback activation of mTOR in the PI-3 kinase pathway by two p70 S6 kinase (S6K1) inhibitors (PF-4708671 and A77 1726, the active metabolite of an immunosuppressive drug leflunomide) or by S6K1 knockdown did not suppress but rather induced autophagy. Suppression of S6K1 activity led to the phosphorylation and activation of AMPK, which then phosphorylated ULK1 at S555. While mTOR feedback activation led to increased phosphorylation of ULK1 at S757, this modification did not the disrupt ULK1-AMPK interaction nor dampen ULK1 S555 phosphorylation and the induction of autophagy. In addition, inhibition of S6K1 activity led to JNK activation, which also contributed to autophagy. 5Z-7-oxozeaenol, a specific inhibitor of TAK1, or TAK1 siRNA blocked A77 1726-induced activation of AMPK and JNK, and LC3 lipidation. Taken together, our study establishes S6K1 as a key player in the PI-3 kinase pathway to suppress autophagy through inhibiting AMPK and JNK in a TAK1-dependent manner.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.