ArticlePloS one2012
Glycogen synthase kinase-3 inhibition sensitizes pancreatic cancer cells to TRAIL-induced apoptosis.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Osthole inhibits GSK-3β/AMPK/mTOR pathway-controlled glycolysis and increases radiosensitivity of subcutaneous transplanted hepatocellular carcinoma in nude mice.Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] · 2024Article
- Glycogen synthase kinase 3β: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?International journal of molecular sciences · 2023Review
- Glycogen Synthase Kinase 3β: A True Foe in Pancreatic Cancer.International journal of molecular sciences · 2022Review
- PET imaging of glycogen synthase kinase-3 in pancreatic cancer xenograft mouse models.American journal of nuclear medicine and molecular imaging · 2022Article
- Lithium and Therapeutic Targeting of GSK-3.Cells · 2021Review
- Review
- Identification of GSK3β inhibitor kenpaullone as a temozolomide enhancer against glioblastoma.Scientific reports · 2019Article
- GSK-3 inhibitors enhance TRAIL-mediated apoptosis in human gastric adenocarcinoma cells.PloS one · 2018Article
- Modulation of glycogen synthase kinase-3β following TRAIL combinatorial treatment in cancer cells.Oncotarget · 2016Article
- Novel roles of Src in cancer cell epithelial-to-mesenchymal transition, vascular permeability, microinvasion and metastasis.Life sciences · 2016Review
- Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells.Cell death & disease · 2014Article
- Targeting Src-mediated Tyr216 phosphorylation and activation of GSK-3 in prostate cancer cells inhibit prostate cancer progression in vitro and in vivo.Oncotarget · 2014Article
- Clinicopathological and biological significance of aberrant activation of glycogen synthase kinase-3 in ovarian cancer.OncoTargets and therapy · 2014Article
- Glycogen Synthase Kinase 3β in Pancreatic Cancer and its Implications in Chemotherapy and Radiation Therapy.Journal of carcinogenesis & mutagenesis · 2013Article
- Activation of Wnt/β-catenin signaling increases apoptosis in melanoma cells treated with trail.PloS one · 2013Article
- Beneficial role of overexpression of TFPI-2 on tumour progression in human small cell lung cancer.FEBS open bio · 2013Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induces apoptosis in a variety of cancer cell lines with little or no effect on normal cells. However, its effect is limited as some cancers including pancreatic cancer show de novo resistance to TRAIL induced apoptosis. In this study we report that GSK-3 inhibition using the pharmacologic agent AR-18, enhanced TRAIL sensitivity in a range of pancreatic and prostate cancer cell lines. This sensitization was found to be caspase-dependent, and both pharmacological and genetic knock-down of GSK-3 isoforms resulted in apoptotic features as shown by cleavage of PARP and caspase-3. Elevated levels of reactive oxygen intermediates and disturbance of mitochondrial membrane potential point to a mitochondrial amplification loop for TRAIL-induced apoptosis after GSK-3 inhibition. Consistent with this, overexpression of anti-apoptotic mitochondrial targets such as Bcl-XL, Mcl-1, and Bcl-2 rescued PANC-1 and PPC-1 cells from TRAIL sensitization. However, overexpression of the caspase-8 inhibitor CrmA also inhibited the sensitizing effects of GSK-3 inhibitor, suggesting an additional role for GSK-3 that inhibits death receptor signaling. Acute treatment of mice bearing PANC-1 xenografts with a combination of AR-18 and TRAIL also resulted in a significant increase in apoptosis, as measured by caspase-3 cleavage. Sensitization to TRAIL occurred despite an increase in β-catenin due to GSK-3 inhibition, suggesting that the approach might be effective even in cancers with dysregulated β-catenin. These results suggest that GSK-3 inhibitors might be effectively combined with TRAIL for the treatment of pancreatic cancer.
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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.