ArticleBiochemical pharmacology2014
Heat shock factor 1 confers resistance to Hsp90 inhibitors through p62/SQSTM1 expression and promotion of autophagic flux.
Article in Biochemical pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 58 citations in OpenAlex.
- YTHDC1 modulates the malignant phenotype of retinoblastoma via SQSTM1-mediated autophagy.Scientific reports · 2026Article
- Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition.Cell death and differentiation · 2025Article
- C-terminal domain dimerization in yeast Hsp90 is moderately modulated by the other domains.Biophysical journal · 2024Article
- Roles of Stress Response in Autophagy Processes and Aging-Related Diseases.International journal of molecular sciences · 2023Review
- The Role of Heat Shock Proteins and Autophagy in Mechanisms Underlying Effects of Sulforaphane on Doxorubicin-Induced Toxicity in HEK293 Cells.Physiological research · 2023Article
- Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications.Pharmaceuticals (Basel, Switzerland) · 2023Article
- HSF1 Attenuates the Release of Inflammatory Cytokines Induced by Lipopolysaccharide through Transcriptional Regulation ofMicrobiology spectrum · 2023Article
- HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review).Oncology reports · 2023Review
- HSF1 and Its Role in Huntington's Disease Pathology.Advances in experimental medicine and biology · 2023Review
- Pterostilbene attenuates intrauterine growth retardation-induced colon inflammation in piglets by modulating endoplasmic reticulum stress and autophagy.Journal of animal science and biotechnology · 2022Article
- HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia.Nature communications · 2022Article
- Targeting HSP90 as a Novel Therapy for Cancer: Mechanistic Insights and Translational Relevance.Cells · 2022Review
- A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.EMBO molecular medicine · 2022Article
- Cardioprotective effect of MLN4924 on ameliorating autophagic flux impairment in myocardial ischemia-reperfusion injury by Sirt1.Redox biology · 2021Article
- Sequestosome 1/p62: A multitasker in the regulation of malignant tumor aggression (Review).International journal of oncology · 2021Review
- KRIBB11 Induces Apoptosis in A172 Glioblastoma Cells via MULE-Dependent Degradation of MCL-1.Molecules (Basel, Switzerland) · 2021Article
- Cooperative treatment effectiveness of ATR and HSP90 inhibition in Ewing's sarcoma cells.Cell & bioscience · 2021Article
- Recent Advances in Genetic and Epigenetic Modulation of Animal Exposure to High Temperature.Frontiers in genetics · 2020Review
- HSF1Base: A Comprehensive Database of HSF1 (Heat Shock Factor 1) Target Genes.International journal of molecular sciences · 2019Article
- Chaperone-mediated autophagy degradation of IGF-1Rβ induced by NVP-AUY922 in pancreatic cancer.Cellular and molecular life sciences : CMLS · 2019Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Heat shock protein 90 (Hsp90) has an important role in many cancers. Biochemical inhibitors of Hsp90 are in advanced clinical development for the treatment of solid and hematological malignancies. At the cellular level, their efficacy is diminished by the fact that Hsp90 inhibition causes activation of heat shock factor 1 (HSF1). We report a mechanism by which HSF1 activation diminishes the effect of Hsp90 inhibitors geldanamycin and 17-allylaminogeldanamycin (17-AAG, tanespimycin). Silencing HSF1 with siRNA or inhibiting HSF1 activity with KRIBB11 lowers the threshold for apoptosis in geldanamycin and 17-AAG-treated cancer cells. Autophagy also mitigates the actions of Hsp90 inhibitors. Blocking autophagy with 3-methyladenine (3-MA), bafilomycin A1, or beclin 1 siRNA also lower the threshold for apoptosis. Exploring a potential relationship between HSF1 and autophagy, we monitored autophagosome formation and autophagic flux in control and HSF1-silenced cells. Results show HSF1 is required for autophagy in Hsp90 inhibitor-treated cells. The reduced autophagy observed in HSF1-silenced cells correlates with enhanced cell death. To investigate how HSF1 promotes autophagy, we monitored the expression of genes involved in the autophagic cascade. These data show that sequestosome 1 (p62/SQSTM1), a protein involved in the delivery of autophagic substrates and nucleation of autophagosomes, is an HSF1-regulated gene. Gene silencing was used to evaluate the significance of p62/SQSTM1 in Hsp90 inhibitor resistance. Cells where p62/SQSTM1 was silenced showed a dramatic increase in sensitivity to Hsp90 inhibitors. Results highlight the importance of HSF1 and HSF1-dependent p62/SQSTM1 expression in resistance Hsp90 inhibitors, underscoring the potential of targeting HSF1 to improve the efficacy of Hsp90 inhibitors in 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.