Heat stress triggers apoptosis by impairing NF-kappaB survival signaling in malignant B cells.
Nuclear factor-kappaB (NF-kappaB) is involved in multiple aspects of oncogenesis and controls cancer cell survival by promoting anti-apoptotic gene expression. The constitutive activation of NF-kappaB 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-kappaB 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-kappaB 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-kappaB regulation. Heat-induced NF-kappaB 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-kappaB aberrations. NF-kappaB 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-kappaB activity are sensitive to heat-induced apoptosis, and suggest that aberrant NF-kappaB regulation may be a marker of heat stress sensitivity in cancer cells.
Belardo
G
G
Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome 00133, Italy.
Piva
R
R
Santoro
M G
MG
D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D006358:Hot Temperature; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D014176:Protein Biosynthesis; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000502:physiology; D044767:Ubiquitin-Protein Ligases
D001897:Boronic Acids; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D011719:Pyrazines; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000069286:Bortezomib; D004247:DNA; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases