ArticleOncogene2015
Combined regulation of mTORC1 and lysosomal acidification by GSK-3 suppresses autophagy and contributes to cancer cell growth.
Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 110 citations in OpenAlex.
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- Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers.Nature communications · 2026Article
- Targeting the GSK-3β/mTOR axis: a novel pharmacological strategy for preeclampsia prevention and treatment.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Overcoming resistance to antibody-drug conjugates: mechanisms and emerging strategies.The oncologist · 2026Review
- Chemically Derived Hepatic Progenitors Are Reprogrammed through Autophagy Suppression by A83-01.International journal of stem cells · 2026Article
- Evaluation of Nrf2/Keap1 Pathway in Patients with Migraine.Medicina (Kaunas, Lithuania) · 2025Article
- PKD3 localizes to late endosomes to maintain Rab7-dependent endolysosomal homeostasis.iScience · 2025Article
- Therapeutic potential of adenosine receptor modulators in cancer treatment.RSC advances · 2025Review
- GSK3β Deficiency Expands Obese Adipose Vasculature to Mitigate Metabolic Disorders.Circulation research · 2025Article
- The cellular adaptor GULP1 interacts with ATG14 to potentiate autophagy and APP processing.Cellular and molecular life sciences : CMLS · 2024Article
- miR-1246-overexpressing exosomes improve UVB-induced photoaging by activating autophagy via suppressing GSK3β.Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology · 2024Article
- Exploring the Neuroprotective Effects of Lithium in Ischemic Stroke: A literature review.International journal of medical sciences · 2024Review
- LncRNAs as nodes for the cross-talk between autophagy and Wnt signaling in pancreatic cancer drug resistance.International journal of biological sciences · 2024Review
- Targeting Pro-Survival Autophagy Enhanced GSK-3β Inhibition-Induced Apoptosis and Retarded Proliferation in Bladder Cancer Cells.Current oncology (Toronto, Ont.) · 2023Article
- Article
- Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+ breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth.Journal of experimental & clinical cancer research : CR · 2023Article
- Glycogen Synthase Kinase 3β: A True Foe in Pancreatic Cancer.International journal of molecular sciences · 2022Review
- Decrypting a path based approach for identifying the interplay between PI3K and GSK3 signaling cascade from the perspective of cancer.Genes & diseases · 2022Review
- Down-regulation of Risa improves podocyte injury by enhancing autophagy in diabetic nephropathy.Military Medical Research · 2022Article
- Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases.Medicinal research reviews · 2022Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
There is controversy over the role of glycogen synthase kinase-3 (GSK-3) in cancer progression. Recent work has implicated GSK-3 in the regulation of mammalian target of rapamycin (mTOR), a known player in malignant transformation. Autophagy, a self-degradation pathway, is inhibited by mTOR and is tightly associated with cell survival and tumor growth. Here we show that GSK-3 suppresses autophagy via mTOR complex-1 (mTORC1) and lysosomal regulation. We show that overexpression of GSK-3 isoforms (GSK-3α and GSK-3β) activated mTORC1 and suppressed autophagy in MCF-7 human breast cancer cells as indicated by reduced beclin-1 levels and upregulation of sequestosome 1 (p62/SQSTM1). Further, overexpression of GSK-3 increased the number of autophagosomes and inhibited autophagic flux. This activity was directly related to reduced lysosomal acidification triggered by GSK-3 (in which GSK-3β has a stronger impact). We found that lysosomal acidification is reduced in MCF-7 cells that also exhibit increased levels of autophagosomes and p62/SQSTM1 and increased activity of mTORC1. Subsequently, treating cells with GSK-3 inhibitors restored lysosomal acidification, enhanced autophagic flux and inhibited mTORC1. Furthermore, GSK-3 inhibitors inhibited cell proliferation. We provide evidence that GSK3-mediated mTORC1 activity and GSK-3-mediated lysosomal acidification occur via distinct pathways, yet both mTORC1 and lysosomes control cell growth. Finally, we show that GSK-3-reduced lysosomal acidification inhibits endocytic clearance as demonstrated by reduced endocytic degradation of the epidermal growth factor receptor. Taken together, our study places GSK-3 as a key regulator coordinating cellular homeostasis. GSK-3 inhibitors may be useful in targeting mTORC1 and lysosomal acidification for cancer therapy.
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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.