ArticleOncotarget2016
JNK pathway inhibition selectively primes pancreatic cancer stem cells to TRAIL-induced apoptosis without affecting the physiology of normal tissue resident stem cells.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 28 citations in OpenAlex.
- Targeting the MAPK Pathway in Cancer.International journal of molecular sciences · 2025Review
- Anoikis resistance in Cancer: Mechanisms, therapeutic strategies, potential targets, and models for enhanced understanding.Cancer letters · 2025Review
- Review
- Inferring regulators of cell identity in the human adult pancreas.NAR genomics and bioinformatics · 2023Article
- Tumor microenvironment enriches the stemness features: the architectural event of therapy resistance and metastasis.Molecular cancer · 2022Review
- JNK inhibitor IX restrains pancreatic cancer through p53 and p21.Frontiers in oncology · 2022Article
- JNK in Tumor Microenvironment: Present Findings and Challenges in Clinical Translation.Cancers · 2021Review
- TRAIL receptor-induced features of epithelial-to-mesenchymal transition increase tumour phenotypic heterogeneity: potential cell survival mechanisms.British journal of cancer · 2021Review
- Therapeutic targeting of pancreatic cancer stem cells by dexamethasone modulation of the MKP-1-JNK axis.The Journal of biological chemistry · 2020Article
- Article
- Tumorigenic de-differentiation: the alternative splicing way.Molecular & cellular oncology · 2020Article
- Inhibition on JNK Mimics Silencing of Wnt-11 Mediated Cellular Response in Androgen-Independent Prostate Cancer Cells.Biology · 2020Article
- Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapy.JCI insight · 2020Article
- Cytotoxic effect of Ad-ephrinA1-caspase-3-T on breast cancer cellsTranslational cancer research · 2019Article
- Therapeutic Strategies Targeting Cancer Stem Cells and Their Microenvironment.Frontiers in oncology · 2019Review
- A graph-embedded deep feedforward network for disease outcome classification and feature selection using gene expression data.Bioinformatics (Oxford, England) · 2018Article
- Identification of bladder cancer prognostic biomarkers using an ageing gene-related competitive endogenous RNA network.Oncotarget · 2017Article
- Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells.Oncotarget · 2017Article
- Repurposing Established Compounds to Target Pancreatic Cancer Stem Cells (CSCs).Medical sciences (Basel, Switzerland) · 2017Review
- Role of Notch signaling pathway in pancreatic cancer.American journal of cancer research · 2017Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveSuccessful treatment of solid cancers mandates targeting cancer stem cells (CSC) without impact on the physiology of normal tissue resident stem cells. C-Jun N-terminal kinase (JNK) signaling has been shown to be of importance in cancer. We test whether JNK inhibition would sensitize pancreatic CSCs to induction of apoptosis via low-dose TNFα-related apoptosis-inducing ligand (TRAIL).
designEffects of JNK inhibition (JNKi) were evaluated in vitro in functional assays, through mRNA and protein expression analysis, and in in vivo mouse studies. CSCs were enriched in anoikis-resistant spheroid culture and analyzed accordingly.
resultsWe confirmed that the JNK pathway is an important regulatory pathway in pancreatic cancer stem cells and further found that JNK inhibition downregulates the decoy receptor DcR1 through IL-8 signaling while upregulating pro-apoptotic death receptors DR4/5, thereby sensitizing cells - even with acquired TRAIL-resistance - to apoptosis induction. Treatment of orthotopic pancreatic cancer xenografts with either gemcitabine, JNKi or TRAIL alone for 4 weeks showed only modest effects compared to control, while the combination of JNKi and TRAIL resulted in significantly lower tumor burden (69%; p < 0.04), reduced numbers of circulating tumor cells, and less distant metastatic events, without affecting the general health of the animals.
conclusionsThe combination of JNKi and TRAIL significantly impacts on CSCs, but leaves regular tissue-resident stem cells unaffected - even under hypoxic stress conditions. This concept of selective treatment of pancreatic CSCs warrants further evaluation.
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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.