ArticleCancer research2014
Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth.
Article in Cancer research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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
30 citing papers in PubMed, 47 citations in OpenAlex.
- CREB1 and GSK3 Isoforms as Potential Adaptive Signaling Nodes in PI3K/Akt/mTOR Inhibitor Treated Philadelphia Chromosome-Positive B-ALL.International journal of molecular sciences · 2026Article
- FASLG Derived from Fibroblasts in Hydroxyapatite-Rich Microenvironment Induces Urothelial Anoikis to Trigger Randall's Plaque Exposure.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeting the GSK-3β/mTOR axis to overcome chemoresistance in gestational choriocarcinoma: molecular mechanisms and therapeutic opportunities.Cancer chemotherapy and pharmacology · 2026Review
- Rapamycin Prevents Sulfate-Reducing Bacteria-Induced Effects on Snail and GSK-3 and Impaired Intestinal Barrier.Microorganisms · 2026Article
- Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.Nature communications · 2023Article
- Therapeutic efficacy of the novel SHP2 degrader SHP2-D26, alone or in combination, against lung cancer is associated with modulation of p70S6K/S6, Bim and Mcl-1.Cancer gene therapy · 2022Article
- Recent Trends in the Incidence of Clear Cell Adenocarcinoma and Survival Outcomes: A SEER Analysis.Frontiers in endocrinology · 2022Article
- mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?Frontiers of medicine · 2021Review
- Glycogen synthase kinase-3β inhibitor SB216763 promotes DNA repair in ischemic retinal neurons.Neural regeneration research · 2021Article
- GSK-3α/β Activity Negatively Regulates MMP-1/9 Expression to SuppressFrontiers in immunology · 2021Article
- An innovative NRF2 nano-modulator induces lung cancer ferroptosis and elicits an immunostimulatory tumor microenvironment.Theranostics · 2021Article
- Searching for the real function of mTOR signaling in the regulation of PD-L1 expression.Translational oncology · 2020Review
- Genetic interaction mapping and exon-resolution functional genomics with a hybrid Cas9-Cas12a platform.Nature biotechnology · 2020Article
- Are Wnt/β-Catenin and PI3K/AKT/mTORC1 Distinct Pathways in Colorectal Cancer?Cellular and molecular gastroenterology and hepatology · 2020Review
- Regulating T Cell Population Alleviates SLE by Inhibiting mTORC1/C2 in MRL/lpr Mice.Frontiers in pharmacology · 2020Article
- Article
- High Throughput Chemical Screening Reveals Multiple Regulatory Proteins on FOXA1 in Breast Cancer Cell Lines.International journal of molecular sciences · 2018Article
- A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma.Neuro-oncology · 2018Article
- In Vitro and In Vivo Antitumor and Anti-Inflammatory Capabilities of the Novel GSK3 and CDK9 Inhibitor ABC1183.The Journal of pharmacology and experimental therapeutics · 2018Article
- Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
mTOR kinase inhibitors that target both mTORC1 and mTORC2 are being evaluated in cancer clinical trials. Here, we report that glycogen synthase kinase-3 (GSK3) is a critical determinant for the therapeutic response to this class of experimental drugs. Pharmacologic inhibition of GSK3 antagonized their suppressive effects on the growth of cancer cells similarly to genetic attenuation of GSK3. Conversely, expression of a constitutively activated form of GSK3β sensitized cancer cells to mTOR inhibition. Consistent with these findings, higher basal levels of GSK3 activity in a panel of human lung cancer cell lines correlated with more efficacious responses. Mechanistic investigations showed that mTOR kinase inhibitors reduced cyclin D1 levels in a GSK3β-dependent manner, independent of their effects on suppressing mTORC1 signaling and cap binding. Notably, selective inhibition of mTORC2 triggered proteasome-mediated cyclin D1 degradation, suggesting that mTORC2 blockade is responsible for GSK3-dependent reduction of cyclin D1. Silencing expression of the ubiquitin E3 ligase FBX4 rescued this reduction, implicating FBX4 in mediating this effect of mTOR inhibition. Together, our findings define a novel mechanism by which mTORC2 promotes cell growth, with potential implications for understanding the clinical action of mTOR kinase inhibitors.
Indexed as
Identifiers
What OpenQuestion holds
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.