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Open AccessArticle

Targeting Hodgkin and Reed–Sternberg Cells with an Inhibitor of Heat-Shock Protein 90: Molecular Pathways of Response and Potential Mechanisms of Resistance

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Oncovirology Laboratory, Bone Marrow Transplantation Center (CEMO), Instituto Nacional de Câncer (INCA), Rio de Janeiro 20230-130, Brazil
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Laboratório Célula-Tronco, CEMO, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20230-130, Brazil
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Laboratório de Pesquisa sobre o Timo, FIOCRUZ, Rio de Janeiro 21040-900, Brazil
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CIFASIS—Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas, Rosario 4237248, Argentina
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IICAR-CONICET Instituto de Ciencias Agrarias de Rosario, Rosario 4237248, Argentina
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Laboratório de Pesquisa Translacional, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20230-130, Brazil
*
Author to whom correspondence should be addressed.
Current Addres: Programa de Pós-Graduação em Anatomia Patológica, Faculdade de Medicina da Universidade Federal do Rio de Janeiro, Rio de Janeiro 21044-020, Brazil.
Int. J. Mol. Sci. 2018, 19(3), 836; https://doi.org/10.3390/ijms19030836
Received: 29 January 2018 / Revised: 26 February 2018 / Accepted: 27 February 2018 / Published: 13 March 2018
(This article belongs to the Special Issue Molecular Chaperones)
Classical Hodgkin lymphoma (cHL) cells overexpress heat-shock protein 90 (HSP90), an important intracellular signaling hub regulating cell survival, which is emerging as a promising therapeutic target. Here, we report the antitumor effect of celastrol, an anti-inflammatory compound and a recognized HSP90 inhibitor, in Hodgkin and Reed–Sternberg cell lines. Two disparate responses were recorded. In KM-H2 cells, celastrol inhibited cell proliferation, induced G0/G1 arrest, and triggered apoptosis through the activation of caspase-3/7. Conversely, L428 cells exhibited resistance to the compound. A proteomic screening identified a total of 262 differentially expressed proteins in sensitive KM-H2 cells and revealed that celastrol’s toxicity involved the suppression of the MAPK/ERK (extracellular signal regulated kinase/mitogen activated protein kinase) pathway. The apoptotic effects were preceded by a decrease in RAS (proto-oncogene protein Ras), p-ERK1/2 (phospho-extracellular signal-regulated Kinase-1/2), and c-Fos (proto-oncogene protein c-Fos) protein levels, as validated by immunoblot analysis. The L428 resistant cells exhibited a marked induction of HSP27 mRNA and protein after celastrol treatment. Our results provide the first evidence that celastrol has antitumor effects in cHL cells through the suppression of the MAPK/ERK pathway. Resistance to celastrol has rarely been described, and our results suggest that in cHL it may be mediated by the upregulation of HSP27. The antitumor properties of celastrol against cHL and whether the disparate responses observed in vitro have clinical correlates deserve further research. View Full-Text
Keywords: celastrol; Hodgkin lymphoma; heat-shock protein 90 (HSP90) inhibition; label-free proteomics; MAPK/ERK pathway; HSP27 celastrol; Hodgkin lymphoma; heat-shock protein 90 (HSP90) inhibition; label-free proteomics; MAPK/ERK pathway; HSP27
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MDPI and ACS Style

Segges, P.; Corrêa, S.; Du Rocher, B.; Vera-Lozada, G.; Krsticevic, F.; Arce, D.; Sternberg, C.; Abdelhay, E.; Hassan, R. Targeting Hodgkin and Reed–Sternberg Cells with an Inhibitor of Heat-Shock Protein 90: Molecular Pathways of Response and Potential Mechanisms of Resistance. Int. J. Mol. Sci. 2018, 19, 836.

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