scholarly journals Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability

2003 ◽  
Vol 370 (3) ◽  
pp. 849-857 ◽  
Author(s):  
Jérôme BOUDEAU ◽  
Maria DEAK ◽  
Margaret A. LAWLOR ◽  
Nick A. MORRICE ◽  
Dario R. ALESSI
Keyword(s):  
Heat Shock ◽  
Protein Kinase ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Kinase Domain ◽  
Cancer Syndrome ◽  
Hsp90 Inhibitors ◽  
Detailed Mechanism ◽  
Anti Cancer ◽  
Hsp90 Chaperone

LKB1 is a widely expressed serine/threonine protein kinase that is mutated in the inherited Peutz—Jeghers cancer syndrome. Recent findings indicate that LKB1 functions as a tumour suppressor, but little is known regarding the detailed mechanism by which LKB1 regulates cell growth. In this study we have purified LKB1 from cells and establish that it is associated with the heat-shock protein 90 (Hsp90) chaperone and the Cdc37 kinase-specific targetting subunit for Hsp90. We demonstrate that Cdc37 and Hsp90 bind specifically to the kinase domain of LKB1. We also perform experiments using Hsp90 inhibitors, which indicate that the association of Hsp90 and Cdc37 with LKB1 regulates LKB1 stability and prevents its degradation by the proteasome. Hsp90 inhibitors are being considered as potential anti-cancer agents. However, our observations indicate that prolonged usage of these drugs could possibly lead to tumour development by decreasing cellular levels of LKB1.

scholarly journals Anti-Cancer Properties of Ginkgolic Acids in Human Nasopharyngeal Carcinoma CNE-2Z Cells via Inhibition of Heat Shock Protein 90

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6575
Author(s):  
Hong-Mei Li ◽  
Hui Ma ◽  
Xiaolong Sun ◽  
Bohan Li ◽  
Chengjiang Cao ◽  
...  
Keyword(s):  
Heat Shock ◽  
Nasopharyngeal Carcinoma ◽  
Heat Shock Protein ◽  
Human Cancer ◽  
Heat Shock Protein 90 ◽  
Migration And Invasion ◽  
Hsp90 Inhibitors ◽  
Human Nasopharyngeal Carcinoma ◽  
Anti Cancer ◽  
Ginkgolic Acids

Ginkgo biloba L. has been used in traditional Chinese medicine (TCM) for thousands of years. However, the anti-cancer properties of ginkgolic acids (GAS) isolated from G. biloba have not been investigated in human nasopharyngeal carcinoma cells. In this study, GAS exhibited an inhibitory effect on the ATPase activity of heat shock protein 90 (Hsp90) and anti-proliferative activities against four human cancer cell lines, with IC50 values ranging from 14.91 to 23.81 μg·mL−1. In vivo experiments confirmed that GAS inhibited tumor growth in CNE-2Z cell-xenografted nude mice with low hepatotoxicity. We further demonstrated that GAS suppressed migration and invasion and induced the apoptosis of CNE-2Z cells by inducing the degradation of Hsp90 client proteins (MMP-2, MMP-9, Her-2, c-Raf, Akt, and Bcl-2). Together, GAS are new Hsp90 inhibitors by binding to Hsp90 (hydrogen bond and hydrophobic interaction). Thus, GAS from G. biloba might represent promising Hsp90 inhibitors for the development of anti-nasopharyngeal carcinoma agents.

Secreted Heat Shock Protein-90α: A More Effective and Safer Target for Anti-Cancer Drugs?

2010 ◽  
Vol 5 (2) ◽  
pp. 121-127 ◽  
Author(s):  
Chieh-Fang Cheng ◽  
Jianhua Fan ◽  
Zhengwei Zhao ◽  
David T. Woodley ◽  
Wei Li
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Cancer Drugs ◽  
Anti Cancer

Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors

2018 ◽  
Vol 61 (10) ◽  
pp. 4397-4411 ◽  
Author(s):  
Doris A. Schuetz ◽  
Lars Richter ◽  
Marta Amaral ◽  
Melanie Grandits ◽  
Ulrich Grädler ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Residence Time ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitors

BCR-ABL point mutants isolated from patients with imatinib mesylate–resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 3041-3044 ◽  
Author(s):  
Mercedes E. Gorre ◽  
Katharine Ellwood-Yen ◽  
Gabriela Chiosis ◽  
Neal Rosen ◽  
Charles L. Sawyers
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Imatinib Mesylate ◽  
Acquired Resistance ◽  
Philadelphia Chromosome ◽  
Heat Shock Protein 90 ◽  
Resistant Mutant ◽  
Kinase Domain ◽  
Molecular Features ◽  
Clinical Resistance

Clinical resistance to imatinib mesylate is commonly observed in patients with advanced Philadelphia chromosome– positive (Ph+) leukemias. Acquired resistance is typically associated with reactivation of BCR-ABL due to kinase domain mutations or gene amplification, indicating that BCR-ABL remains a viable target for inhibition in these patients. Strategies for overcoming resistance can be envisioned through exploitation of other molecular features of the BCR-ABL protein, such as its dependence on the molecular chaperone heat shock protein 90 (Hsp90). To determine whether inhibition of Hsp90 could induce degradation of imatinib mesylate–resistant, mutant BCR-ABL proteins, hematopoietic cells expressing 2 mutant BCR-ABL proteins found in imatinib mesylate–resistant patients (T315I and E255K) were examined for sensitivity to geldanamycin and 17-allylaminogeldanamycin (17-AAG). Both compounds induced the degradation of wild-type and mutant BCR-ABL and inhibited cell growth, with a trend indicating more potent activity against mutant BCR-ABL proteins. These data support clinical investigations of 17-AAG in imatinib mesylate–resistant Ph+ leukemias.

Identification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary Approach

2016 ◽  
Vol 22 (37) ◽  
pp. 13236-13250 ◽  
Author(s):  
Maria G. Chini ◽  
Nicola Malafronte ◽  
Maria C. Vaccaro ◽  
Maria J. Gualtieri ◽  
Antonio Vassallo ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Multidisciplinary Approach ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitors
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