ArticleProceedings of the National Academy of Sciences of the United States of America2014
Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 135 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
135 citing papers in PubMed, 2 syntheses or guidelines pooled it, 221 citations in OpenAlex.
- Association of metformin use with risk and survival outcome of esophageal cancer in patients with diabetes: A systematic review and meta-analysis.PloS one · 2025 · on this mapPooled it
- AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review.Cells · 2021Pooled it
- Constitutive AMPK activation prevents hepatocellular carcinoma development through inhibition of HNF4α activity.Science advances · 2026Article
- Oblique-incidence reflectivity difference technology identifies the antiviral drug Ribavirin as an inhibitor of lung tumor progression by targeting AMPK signaling.Journal of pharmaceutical analysis · 2026Article
- Targeting Metabolic Vulnerabilities Reveals Hexokinase 2 as a Key Mediator of Resistance to Osimertinib in Non-Small Cell Lung Cancer Models.ACS pharmacology & translational science · 2025Article
- A system-level model reveals that transcriptional stochasticity is required for hematopoietic stem cell differentiation.NPJ systems biology and applications · 2024Article
- New concepts in the roles of AMPK in adipocyte stem cell biology.Essays in biochemistry · 2024Review
- Molecular pathways and therapeutic targets linked to triple-negative breast cancer (TNBC).Molecular and cellular biochemistry · 2024Review
- Research Progress on the Use of Metformin in Leukemia Treatment.Current treatment options in oncology · 2024Review
- Molecular mechanisms of action of metformin: latest advances and therapeutic implications.Clinical and experimental medicine · 2023Review
- Autophagy Modulation and Its Implications on Glioblastoma Treatment.Current issues in molecular biology · 2023Review
- Purine Nucleotide Alterations in Tumoral Cell Lines Maintained with Physiological Levels of Folic Acid.International journal of molecular sciences · 2023Article
- Efficacy and safety of metformin plus low-dose temozolomide in patients with recurrent or refractory glioblastoma: a randomized, prospective, multicenter, double-blind, controlled, phase 2 trial (KNOG-1501 study).Discover oncology · 2023Article
- Metabolic Reprogramming and Potential Therapeutic Targets in Lymphoma.International journal of molecular sciences · 2023Review
- AICAR Ameliorates Non-Alcoholic Fatty Liver Disease via Modulation of the HGF/NF-κB/SNARK Signaling Pathway and Restores Mitochondrial and Endoplasmic Reticular Impairments in High-Fat Diet-Fed Rats.International journal of molecular sciences · 2023Article
- Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study.Molecular biomedicine · 2022Review
- Metabolites of De Novo Purine Synthesis: Metabolic Regulators and Cytotoxic Compounds.Metabolites · 2022Article
- Brain pharmacokinetics and metabolism of the AMP-activated protein kinase selective inhibitor SBI-0206965, an investigational agent for the treatment of glioblastoma.Investigational new drugs · 2022Article
- Regulation and role of CAMKK2 in prostate cancer.Nature reviews. Urology · 2022Review
- A Novel Classification Model for Lower-Grade Glioma Patients Based on Pyroptosis-Related Genes.Brain sciences · 2022Article
75 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
19 authors at 8 institutions in 3 countries.
Funding
Abstract
The multifunctional AMPK-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that plays an important role in cell proliferation, growth, and survival. It remains unclear whether AMPK functions as a tumor suppressor or a contextual oncogene. This is because although on one hand active AMPK inhibits mammalian target of rapamycin (mTOR) and lipogenesis--two crucial arms of cancer growth--AMPK also ensures viability by metabolic reprogramming in cancer cells. AMPK activation by two indirect AMPK agonists AICAR and metformin (now in over 50 clinical trials on cancer) has been correlated with reduced cancer cell proliferation and viability. Surprisingly, we found that compared with normal tissue, AMPK is constitutively activated in both human and mouse gliomas. Therefore, we questioned whether the antiproliferative actions of AICAR and metformin are AMPK independent. Both AMPK agonists inhibited proliferation, but through unique AMPK-independent mechanisms and both reduced tumor growth in vivo independent of AMPK. Importantly, A769662, a direct AMPK activator, had no effect on proliferation, uncoupling high AMPK activity from inhibition of proliferation. Metformin directly inhibited mTOR by enhancing PRAS40's association with RAPTOR, whereas AICAR blocked the cell cycle through proteasomal degradation of the G2M phosphatase cdc25c. Together, our results suggest that although AICAR and metformin are potent AMPK-independent antiproliferative agents, physiological AMPK activation in glioma may be a response mechanism to metabolic stress and anticancer agents.
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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.