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Lymphoma

Heat stress triggers apoptosis by impairing NF-κB survival signaling in malignant B cells

Leukemia volume 24, pages 187–196 (2010)Cite this article

Abstract

Nuclear factor-κB (NF-κB) is involved in multiple aspects of oncogenesis and controls cancer cell survival by promoting anti-apoptotic gene expression. The constitutive activation of NF-κB in several types of cancers, including hematological malignancies, has been implicated in the resistance to chemo- and radiation therapy. We have previously reported that cytokine- or virus-induced NF-κB activation is inhibited by chemical and physical inducers of the heat shock response (HSR). In this study we show that heat stress inhibits constitutive NF-κB DNA-binding activity in different types of B-cell malignancies, including multiple myeloma, activated B-cell-like (ABC) type of diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma presenting aberrant NF-κB regulation. Heat-induced NF-κB inhibition leads to rapid downregulation of the anti-apoptotic protein cellular inhibitor-of-apoptosis protein 2 (cIAP-2), followed by activation of caspase-3 and cleavage of the caspase-3 substrate poly(adenosine diphosphate ribose)polymerase (PARP), causing massive apoptosis under conditions that do not affect viability in cells not presenting NF-κB aberrations. NF-κB inhibition by the proteasome inhibitor bortezomib and by short-hairpin RNA (shRNA) interference results in increased sensitivity of HS-Sultan B-cell lymphoma to hyperthermic stress. Altogether, the results indicate that aggressive B-cell malignancies presenting constitutive NF-κB activity are sensitive to heat-induced apoptosis, and suggest that aberrant NF-κB regulation may be a marker of heat stress sensitivity in cancer cells.

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Acknowledgements

This work was supported by the Italian Ministry of University and Scientific Research (MIUR), the Italian Ministry of Public Health (ISS projects Lotta ai Tumori), the EU EICOSANOX project and Regione Piemonte (A361 Project). We thank Dr Cristina Ferreri for technical help.

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Authors and Affiliations

  1. Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, Italy

    G Belardo & M G Santoro

  2. Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, via Fosso del Cavaliere 100, Rome, Italy

    G Belardo & M G Santoro

  3. Department of Biomedical Sciences and Human Oncology, Center for Experimental Research and Medical Studies (CERMS), University of Turin, Turin, Italy

    R Piva

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  1. G Belardo
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Correspondence to M G Santoro.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Belardo, G., Piva, R. & Santoro, M. Heat stress triggers apoptosis by impairing NF-κB survival signaling in malignant B cells. Leukemia 24, 187–196 (2010). https://doi.org/10.1038/leu.2009.227

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