ArticlePLoS biology2014
De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling.
Article in PLoS biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 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
76 citing papers in PubMed, 113 citations in OpenAlex.
- Neuroprotective role of NRF2 activation against ER Stress-Mediated apoptosis in obstructive sleep apnea.The Journal of biological chemistry · 2026Article
- ABCG2-autophagy regulatory axis in cancer stem cells: implication in cancer metastasis, recurrence and chemotherapy resistance.Cell communication and signaling : CCS · 2026Review
- Cancer Cell Dormancy and Chemotherapy Resistance.Journal of Cancer · 2026Review
- EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer.EMBO molecular medicine · 2025Article
- PERK-dependent reciprocal crosstalk between ER and non-centrosomal microtubules coordinates ER architecture and cell shape.Cell reports · 2025Article
- ER stress and/or ER-phagy in drug resistance? Three coincidences are proof.Cell communication and signaling : CCS · 2025Review
- Review
- Endoplasmic Reticulum Stress: Triggers Microenvironmental Regulation and Drives Tumor Evolution.Cancer medicine · 2025Review
- Homeostasis control in health and disease by the unfolded protein response.Nature reviews. Molecular cell biology · 2025Review
- Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to cancer cell apoptosis and renders synergism to overcome paclitaxel resistance in breast cancer cells.Cancer cell international · 2024Article
- The unfolded protein response machinery in glioblastoma genesis, chemoresistance and as a druggable target.CNS neuroscience & therapeutics · 2024Review
- NCI 159456 PERK Inhibitor as a Targeted Therapy for Lung Cancer: An In Vitro Study.Biomedicines · 2024Article
- Targeting the key players of phenotypic plasticity in cancer cells by phytochemicals.Cancer metastasis reviews · 2024Review
- Emerging mechanisms of the unfolded protein response in therapeutic resistance: from chemotherapy to Immunotherapy.Cell communication and signaling : CCS · 2024Review
- Endoplasmic reticulum stress and quality control in relation to cisplatin resistance in tumor cells.Frontiers in pharmacology · 2024Review
- How to deal with frenemy NRF2: Targeting NRF2 for chemoprevention and cancer therapy.Journal of food and drug analysis · 2023Review
- The unfolded protein response (UPR) pathway: the unsung hero in breast cancer management.Apoptosis : an international journal on programmed cell death · 2023Review
- The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis.Molecules and cells · 2023Review
- Emerging Role of NRF2 Signaling in Cancer Stem Cell Phenotype.Molecules and cells · 2023Review
- CFTR reduces the proliferation of lung adenocarcinoma and is a strong predictor of survival in both smokers and non-smokers.Journal of cancer research and clinical oncology · 2022Article
16 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Malignant carcinomas that recur following therapy are typically de-differentiated and multidrug resistant (MDR). De-differentiated cancer cells acquire MDR by up-regulating reactive oxygen species (ROS)-scavenging enzymes and drug efflux pumps, but how these genes are up-regulated in response to de-differentiation is not known. Here, we examine this question by using global transcriptional profiling to identify ROS-induced genes that are already up-regulated in de-differentiated cells, even in the absence of oxidative damage. Using this approach, we found that the Nrf2 transcription factor, which is the master regulator of cellular responses to oxidative stress, is preactivated in de-differentiated cells. In de-differentiated cells, Nrf2 is not activated by oxidation but rather through a noncanonical mechanism involving its phosphorylation by the ER membrane kinase PERK. In contrast, differentiated cells require oxidative damage to activate Nrf2. Constitutive PERK-Nrf2 signaling protects de-differentiated cells from chemotherapy by reducing ROS levels and increasing drug efflux. These findings are validated in therapy-resistant basal breast cancer cell lines and animal models, where inhibition of the PERK-Nrf2 signaling axis reversed the MDR of de-differentiated cancer cells. Additionally, analysis of patient tumor datasets showed that a PERK pathway signature correlates strongly with chemotherapy resistance, tumor grade, and overall survival. Collectively, these results indicate that de-differentiated cells up-regulate MDR genes via PERK-Nrf2 signaling and suggest that targeting this pathway could sensitize drug-resistant cells to chemotherapy.
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.