ABSTRACT
Understanding the mechanisms that control stress-induced apoptosis is critical to explain how tumours respond to treatment, as cancer cells frequently escape drug toxicity by regulating stress response through heat shock protein (HSP) expression. The overexpression of Hsp72, in particular, results in increased incidence of cell transformation, and correlates with poor prognosis in a wide range of cancers. We have shown that Hsp72 assists folding of oncogenic NPM-ALK kinase in anaplastic large-cell lymphomas (ALCLs), but its role in the maintenance of the malignant phenotype remains uncertain. Therefore, we assessed Hsp72 expression in ALCLs, investigating more in detail the mechanisms that regulate its status and activity. We found that Hsp72 is unique among the HSPs involved in tumourigenesis to be overexpressed in ALK(+) tumours and cell lines and to be induced by stress. Different from other HSPs, Hsp72 prevents cell injury, Bax activation and death by apoptosis in ALK(+) cells, acting both upstream and downstream of mitochondria. Conversely, Hsp72 is underexpressed in ALK(-) ALCL cells, and it is unable to protect cells from apoptosis under stress. Moreover, when Hsp72 expression is reduced following NPM-ALK inhibition, lymphoma cells undergo apoptosis, demonstrating the importance of Hsp72 in regulating ALCL stress response and drug sensitivity.
Subject(s)
Apoptosis , HSP72 Heat-Shock Proteins/metabolism , Lymphoma, Large-Cell, Anaplastic/metabolism , Lymphoma, Large-Cell, Anaplastic/pathology , Mitochondria/pathology , Nuclear Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Anaplastic Lymphoma Kinase , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Blotting, Western , Cell Proliferation , Child , Down-Regulation , Gene Expression Profiling , HSP72 Heat-Shock Proteins/genetics , Humans , Immunoenzyme Techniques , Nuclear Proteins/genetics , Nucleophosmin , Oligonucleotide Array Sequence Analysis , Phosphorylation , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptor Protein-Tyrosine Kinases/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Tissue Array AnalysisSubject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Boronic Acids/pharmacology , Cell Cycle/drug effects , Lymphoma, Large B-Cell, Diffuse/pathology , Proteasome Inhibitors , Pyrazines/pharmacology , Bortezomib , Cell Division/genetics , Cell Line, Tumor , Enzyme Inhibitors/pharmacology , G2 Phase/drug effects , Humans , Proteasome Endopeptidase ComplexABSTRACT
A method for positioning the cardiac end of a ventriculoatrial shunt with the aid of echocardiography is described. This simple procedure has resulted in safe and accurate shunt placement in infants.
