ArticleNature medicine2015
A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease.
Article in Nature medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 113 citations in OpenAlex.
- Targeting HSP90 in cancer: advances in the development of inhibitors, mechanisms of action, and therapeutic applications.Molecular cancer · 2026Review
- Review
- Cushing's Disease in the Animal Kingdom: Translational Insights for Human Medicine.International journal of molecular sciences · 2025Review
- Review
- A Brief Overview of Molecular Biology in Pituitary Adenomas with a Focus on Aggressive Lesions.International journal of molecular sciences · 2025Review
- Cushing syndrome.Nature reviews. Disease primers · 2025Review
- Cell Membrane Hybrid Liposome-Targeted Delivery of the Heat Shock Protein 90 C-Terminal Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis.ACS pharmacology & translational science · 2024Article
- Silibinin Targeting Heat Shock Protein 90 Represents a Novel Approach to Alleviate Nonalcoholic Fatty Liver Disease by Simultaneously Lowering Hepatic Lipotoxicity and Enhancing Gut Barrier Function.ACS pharmacology & translational science · 2024Article
- Epigenetic Mechanisms Modulated by Glucocorticoids With a Focus on Cushing Syndrome.The Journal of clinical endocrinology and metabolism · 2024Review
- Current and Emerging Pharmacological Therapies for Cushing's Disease.Current pharmaceutical design · 2024Review
- Silibinin, a potential fasting mimetic, inhibits hepatocellular carcinoma by triggering extrinsic apoptosis.MedComm · 2024Article
- Article
- Review
- Silibinin, an HSP90 Inhibitor, on Human ACTH-Secreting Adenomas.Neuroendocrinology · 2023Article
- Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors.Cancers · 2022Article
- Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing's Syndrome.Endocrine reviews · 2022Review
- The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas.International journal of molecular sciences · 2022Review
- Current and Emerging Medical Therapies in Pituitary Tumors.Journal of clinical medicine · 2022Review
- USP8, USP48, and BRAF mutations differ in their genotype-phenotype correlation in Asian Indian patients with Cushing's disease.Endocrine · 2022Article
- Synthesis and antitumor activity of novel silibinin and 2,3-dehydrosilybin derivatives with carbamate groups.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2022Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
One function of the glucocorticoid receptor (GR) in corticotroph cells is to suppress the transcription of the gene encoding proopiomelanocortin (POMC), the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing disease is a neuroendocrine condition caused by partially glucocorticoid-resistant corticotroph adenomas that excessively secrete ACTH, which leads to hypercortisolism. Mutations that impair GR function explain glucocorticoid resistance only in sporadic cases. However, the proper folding of GR depends on direct interactions with the chaperone heat shock protein 90 (HSP90, refs. 7,8). We show here that corticotroph adenomas overexpress HSP90 compared to the normal pituitary. N- and C-terminal HSP90 inhibitors act at different steps of the HSP90 catalytic cycle to regulate corticotroph cell proliferation and GR transcriptional activity. C-terminal inhibitors cause the release of mature GR from HSP90, which promotes its exit from the chaperone cycle and potentiates its transcriptional activity in a corticotroph cell line and in primary cultures of human corticotroph adenomas. In an allograft mouse model, the C-terminal HSP90 inhibitor silibinin showed anti-tumorigenic effects, partially reverted hormonal alterations, and alleviated symptoms of Cushing disease. These results suggest that the pathogenesis of Cushing disease caused by overexpression of heat shock proteins and consequently misregulated GR sensitivity may be overcome pharmacologically with an appropriate HSP90 inhibitor.
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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.