Consequences of heat shock protein 72 (Hsp72) expression and activity on stress-induced apoptosis in CD30+ NPM–ALK+ anaplastic large-cell lymphomas
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 i...
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Published in | Leukemia Vol. 26; no. 6; pp. 1375 - 1382 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.06.2012
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0887-6924 1476-5551 |
DOI: | 10.1038/leu.2011.367 |