ArticleOncotarget2016
Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 53 citations in OpenAlex.
- Hallmarks of epithelial-mesenchymal plasticity in cancer.Molecular cancer · 2026Review
- Targeting the MEK/ERK Pathway to Suppress P-Glycoprotein and Reverse Carfilzomib Resistance in Multiple Myeloma.International journal of molecular sciences · 2025Article
- Nrf2 Drives Epigenetic Reprogramming and Acts as the Master Regulator of KLF4 Expression and Activity in Arsenic-Induced Transformation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma.Clinical and experimental medicine · 2025Review
- Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2-P62 Axis and Suppressing IRF4 Transcription.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- The Aryl Hydrocarbon Receptor and Its Crosstalk: A Chemopreventive Target of Naturally Occurring and Modified Phytochemicals.Molecules (Basel, Switzerland) · 2024Review
- Different Strategies to Overcome Resistance to Proteasome Inhibitors-A Summary 20 Years after Their Introduction.International journal of molecular sciences · 2024Review
- Article
- Carbamate compounds induced toxic effects by affecting Nrf2 signaling pathways.Toxicology reports · 2024Review
- Investigation of Non-Coding RNA-Related Autophagy Alterations in Drug-Resistant Multiple Myeloma Plasma Cells.Iranian journal of pathology · 2024Article
- TAZ upregulates MIR-224 to inhibit oxidative stress response in multiple myeloma.Cancer reports (Hoboken, N.J.) · 2023Article
- The mitochondrial pyruvate carrier complex potentiates the efficacy of proteasome inhibitors in multiple myeloma.Blood advances · 2023Article
- DNMT3A R882H mutation drives daunorubicin resistance in acute myeloid leukemia via regulating NRF2/NQO1 pathway.Cell communication and signaling : CCS · 2022Article
- Article
- Article
- Vitamin C Sensitizes Pancreatic Cancer Cells to Erastin-Induced Ferroptosis by Activating the AMPK/Nrf2/HMOX1 Pathway.Oxidative medicine and cellular longevity · 2022Article
- Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors.Frontiers in oncology · 2022Review
- Role of Nrf2 in Pancreatic Cancer.Antioxidants (Basel, Switzerland) · 2021Review
- Review
- Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma.Cellular and molecular life sciences : CMLS · 2021Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiation factor gene EIF4E3 was among the Nrf2 target genes upregulated in LP-1/Cfz cells, suggesting existence of a positive feedback loop. In line with this, we found that siRNA knockdown of eIF4E3 decreased Nrf2 protein levels. On the other hand, elevated SQSTM1/p62 levels were due at least in part to activation of the PERK-eIF2α pathway. LP-1/Cfz cells had decreased levels of reactive oxygen species as well as elevated levels of fatty acid oxidation and prosurvival autophagy. Genetic and pharmacologic inhibition of the Nrf2-EIF4E3 axis or the PERK-eIF2α pathway, disruption of redox homeostasis or inhibition of fatty acid oxidation or autophagy conferred sensitivity to carfilzomib. Our findings were supported by clinical data where increased EIF4E3 expression was predictive of Nrf2 target gene upregulation in a subgroup of patients with chemoresistant minimal residual disease and relapsed/refractory MM. Thus, our data offer a preclinical rationale for including inhibitors of the SQSTM1/p62-Nrf2 pathway to the treatment regimens for certain advanced stage MM patients.
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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.