ArticleCancer biology & therapy2010
ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells.
Article in Cancer biology & therapy, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 59 citations in OpenAlex.
- Mechanisms and therapeutic opportunities of the ribotoxic stress response in cancer.Molecular oncology · 2026Review
- Article
- Arrestin-3 sca-olds multiple MAP3Ks driving stress-induced JNK3 activation and cell death.bioRxiv : the preprint server for biology · 2026Article
- Context-dependent translation inhibition as a cancer therapeutic modality.Nature communications · 2026Article
- ZAK activation at the collided ribosome.Nature · 2026Article
- ZAKα Induces Pyroptosis of Colonic Epithelium Via the Caspase-11/GSDMD Pathway to Aggravate Colitis.Inflammation · 2025Article
- Mycotoxin-Caused Intestinal Toxicity: Underlying Molecular Mechanisms and Further Directions.Toxics · 2025Review
- Cell cycle regulation by the ribotoxic stress response.Trends in cell biology · 2025Review
- Review
- Article
- Initiation of a ZAKα-dependent ribotoxic stress response by the innate immunity endoribonuclease RNase L.Cell reports · 2024Article
- Emerging Role of GCN1 in Disease and Homeostasis.International journal of molecular sciences · 2024Review
- ZAKα/P38 kinase signaling pathway regulates hematopoiesis by activating the NLRP1 inflammasome.EMBO molecular medicine · 2023Article
- Dexpanthenol ameliorates doxorubicin-induced lung injury by regulating endoplasmic reticulum stress and apoptosis.Naunyn-Schmiedeberg's archives of pharmacology · 2023Article
- Rutin and Quercetin Counter Doxorubicin-Induced Liver Toxicity in Wistar RatsOxidative medicine and cellular longevity · 2022Article
- Spatial-proteomics reveals phospho-signaling dynamics at subcellular resolution.Nature communications · 2021Article
- Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury.Research in pharmaceutical sciences · 2021Article
- Mucosal ribosomal stress-induced PRDM1 promotes chemoresistance via stemness regulation.Communications biology · 2021Article
- Ribosomal stress-surveillance: three pathways is a magic number.Nucleic acids research · 2020Review
- A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis.Biochemistry. Biokhimiia · 2020Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Doxorubicin is an anthracycline drug that is one of the most effective and widely used anticancer agents for the treatment of both hematologic and solid tumors. The stress-activated protein kinases (SAPKs) are frequently activated by a number of cancer chemotherapeutics. When phosphorylated, the SAPKs initiate a cascade that leads to the production of proinflammatory cytokines. Some inhibitors of protein synthesis, known as ribotoxic stressors, coordinately activate SAPKs and lead to apoptotic cell death. We demonstrate that doxorubicin effectively inhibits protein synthesis, activates SAPKs, and causes apoptosis. Ribotoxic stressors share a common mechanism in that they require ZAK, an upstream MAP3K, to activate the pro-apoptotic and proinflammatory signaling pathways that lie downstream of SAPKs. By employing siRNA mediated knockdown of ZAK or administration of sorafenib and nilotinib, kinase inhibitors that have a high affinity for ZAK, we provide evidence that ZAK is required for doxorubicin-induced proinflammatory and apoptotic responses in HaCaT cells, a pseudo-normal keratinocyte cell line, but not in HeLa cells, a cancerous cell line. ZAK has two different isoforms, ZAK-α (91 kDa) and ZAK-β (51 kDa). HaCaT or HeLa cells treated with doxorubicin and immunoblotted for ZAK displayed a progressive decrease in the ZAK-α band and the appearance of ZAK-β bands of larger size. Abrogation of these changes after exposure of cells to sorafenib and nilotinib suggests that these alterations occur following stimulation of ZAK. We suggest that ZAK inhibitors such as sorafenib or nilotinib may be effective when combined with doxorubicin to treat cancer patients.
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Registered trials
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