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01.12.2015 | Letter to the Editor | Ausgabe 1/2015 Open Access

Journal of Hematology & Oncology 1/2015

Heat shock factor 1 is a potent therapeutic target for enhancing the efficacy of treatments for multiple myeloma with adverse prognosis

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2015
Autoren:
Sophie Bustany, Julie Cahu, Géraldine Descamps, Catherine Pellat-Deceunynck, Brigitte Sola
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13045-015-0135-3) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SB and BS designed the research; SB, JC, GD, CPD, and BS acquired the data; SB, JC, GD, CPD, and BS analyzed the data; and SB and BS wrote the paper. All authors approved the final version of the paper.
Abbreviations
Ab
Antibody
BCL2
B-cell lymphoma 2
BMPC
Normal bone marrow plasma cells
CI
Combination index
HMCL
Human myeloma cell line
HSF1
Heat shock transcription factor 1
HSP
Heat shock protein
MCL1
Myeloid cell leukemia 1
MM
Multiple myeloma
PARP
Poly (ADP-ribose) polymerase
VER-155008
5′-O-[(4-Cyanophenyl)methyl]-8-[[(3,4-dichlorophenyl)methyl]amino]-adenosine
17-AAG
17-Allylamino-17-demethoxy-geldanamycin

Findings

Deregulated expression of heat shock proteins (HSPs) and heat shock transcription factor 1 (HSF1) plays a major role in the pathogenesis of multiple myeloma (MM) [ 1, 2]. In turn, several HSP/HSF1 inhibitors are currently undergoing preclinical and/or clinical investigations [ 3, 4].
We used human myeloma cell lines (HMCLs) belonging to several molecular groups [ 5, 6] to analyze HSP expression (Figure  1A). HSP90 and its co-chaperone HSP70 were constitutively expressed in all HMCLs. HSP27 expression was more heterogeneous. Using the Little Rock public database [ 6], we investigated whether the expression of HSPB1, HSPA4, and HSP90AA1 genes varied according to the MM molecular classification. Compared to normal bone marrow plasma cells, HSP genes were constantly overexpressed (Figure  1B). HSPB1 and HSP90AA1 expressions were higher in the groups with bad prognosis, PR/MS/MF, and HSPA4 expression in the HY/MF/PR groups. The material and methods used in the study are detailed in Additional file 1.
We studied the sensitivity of HMCLs towards 17-AAG that targets HSP90 or KNK-437 (an inhibitor of HSF1 and, in turn, of both HSP70 and HSP27). HMCLs were constantly sensitive to both inhibitors although heterogeneously responding (Figure  1C, Additional files 2 and 3). This suggests that inhibiting HSPs might potentiate drug treatments for MM patients.
HSPs contribute to MM survival by impairing the mitochondria- and endoplasmic reticulum (ER)-mediated apoptotic pathways [ 7, 8]. In L363 cells (MF group), HSP70 expression decreased following KNK-437 treatment while increased after 17-AAG (Figure  1D). As confirmed by the activation of procaspases 9 and 3 and the cleavage of PARP, a mitochondrial-mediated apoptosis was triggered. The expression of anti-apoptotic BCL2 and MCL1 proteins decreased after KNK-437 treatment. Last, both inhibitors induced a decrease of the procaspase 4, thus favoring an ER stress.
We investigated the capacity of HSP90/HSF1 inhibitors to co-operate with common antimyeloma drugs (bortezomib, dexamethasone, or lenalidomide). We calculated the combination index using the method of Chou [ 9]. Both inhibitors antagonized lenalidomide effects, suggesting that those associations could be harmful (Additional file 4). The combination of KNK-437 with bortezomib or dexamethasone was highly potent in all cell lines tested but not the association 17-AAG/dexamethasone. The activation of procaspases 9/3 and the decrease of MCL1 and BCL2 levels were enhanced by the association KNK-437/bortezomib but not the association 17-AAG/bortezomib (Figure  2A). VER-155008, a strict HSP70 inhibitor, combined with bortezomib was no more potent for inducing apoptosis (Figure  2B).
We tested the response of HMCLs co-cultured with human bone marrow stromal cells (HS-5 cells). The percentage of apoptotic cells was enhanced by the co-treatment KNK-437/bortezomib (Figure  2B). This indicates that KNK-437/bortezomib combined therapy could overcome cell adhesion-mediated drug resistance.
We finally analyzed the response of primary cells isolated from four MM or plasma cell leukemia (PCL) patients (Additional file 5) towards KNK-437 and bortezomib after CD138 staining [ 10]. For patient #3, the fraction of CD138+ cells decreased in the presence of both drugs, revealing an additive effect in primary cells (Figure  2C). Similar results were obtained for other MM primary samples (Additional file 6).
Our results strongly suggest that HSF1 inhibitors might be promising agents in association with bortezomib-based therapeutic protocols to treat MM patients with adverse prognosis or in relapse.

Acknowledgements

The authors thank A Barbaras and Y Zozulya for the technical assistance with cell cultures, the tumorothèque of IRCNA (CHU and ICO, Nantes, France) for providing us with the purified myeloma cells and the technical platforms of flow cytometry (SFR ICORE, Université de Caen Basse-Normandie, PT Cytocell, SFR Bonamy, Nantes). Celgene Corporation (Summit, NJ) provided the lenalidomide. This work was supported by the Fondation de France (Engt n°201200029144) and Comité de la Manche de la Ligue contre le Cancer (to BS). SB was supported by the Ministère de l’Enseignement Supérieur et de la Recherche and JC by the Conseil Régional de Basse-Normandie.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
The Creative Commons Public Domain Dedication waiver ( https://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SB and BS designed the research; SB, JC, GD, CPD, and BS acquired the data; SB, JC, GD, CPD, and BS analyzed the data; and SB and BS wrote the paper. All authors approved the final version of the paper.

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