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Endothelin-1 (ET-1) induces resistance to bortezomib in human multiple myeloma cells via a pathway involving the ETB receptor and upregulation of proteasomal activity

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Bortezomib (BTZ) is used for the treatment of multiple myeloma (MM). However, a significant proportion of patients may be refractory to the drug. This study aimed to investigate whether the endothelin (ET-1) axis may act as an escape mechanism to treatment with bortezomib in MM cells.

Methods

NCI-H929 and RPMI-8226 (human MM cell lines) were cultured with or without ET-1, BTZ, and inhibitors of the endothelin receptors. ET-1 levels were determined by ELISA, while the protein levels of its receptors and of the PI3K and MAPK pathways’ components by western blot. Effects of ET-1 on cell proliferation were studied by MTT and on the ubiquitin proteasome pathway by assessing the chymotryptic activity of the 20S proteasome in cell lysates.

Results

Endothelin receptors A and B (ETAR and ETBR, respectively) were found to be expressed in both cell lines, with the RPMI-8226 cells that are considered resistant to BTZ, expressing higher levels of ETBR and in addition secreting ET-1. Treatment of the NCI-H929 cells with ET-1 increased proliferation, while co-incubation of these cells with ET-1 and BTZ decreased BTZ efficacy with concomitant upregulation of 20S proteasomal activity. Si-RNA silencing or chemical blockade of ETBR abrogated the protective effects of ET-1. Finally, data suggest that the predominant signaling pathway involved in ET-1/ETBR-induced BTZ resistance in MM cells may be the MAPK pathway.

Conclusion

Our data suggest a possible role of the ET-1/ETBR axis in regulating the sensitivity of MM cells to BTZ. Thus, combining bortezomib with strategies to target the ET-1 axis could prove to be a novel promising therapeutic approach in MM.

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Abbreviations

Akt:

Protein kinase B

BTZ:

Bortezomib

DMSO:

Dimethyl sulfoxide

EGF:

Epidermal growth factor

Erk1/2 (p44/42):

Extracellular signal-regulated kinase

ET-1:

Endothelin-1

ET-2:

Endothelin-2

ET-3:

Endothelin-3

ETAR:

Endothelin receptor A

ETBR:

Endothelin receptor B

FBS:

Foetal bovine serum

GPCR:

G-protein coupled receptor

HMCLs:

Human multiple myeloma cell lines

HY:

Hyperdiploid class

IGF-1:

Insulin-like growth factor 1

LB:

Low bone disease class

MAPK:

Mitogen-activated protein kinase

MM:

Multiple myeloma

MTT:

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

NEP/CD10:

Neuropeptidase

NF-kB:

Nuclear factor kB

NP’s:

Neuropeptides

P70S6K:

p70S6 Kinase

PI:

Proteasome inhibitor

PI3-K:

Phosphoinositide 3-kinase

PS-341:

Bortezomib

UPS:

Ubiquitin proteasome system

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    1. Department of Medical Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41110, Larissa, Greece

      Maria Vaiou & Christos Papandreou

    2. Laboratory of Biochemistry, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41110, Larissa, Greece

      Evanthia Pangou & Panagiotis Liakos

    3. Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41110, Larissa, Greece

      Nikos Sakellaridis & Konstantinos Dimas

    4. Department of Hematology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41110, Larissa, Greece

      George Vassilopoulos

    Authors
    1. Maria Vaiou
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    2. Evanthia Pangou
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    3. Panagiotis Liakos
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    4. Nikos Sakellaridis
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    5. George Vassilopoulos
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    6. Konstantinos Dimas
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    7. Christos Papandreou
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    Correspondence to Konstantinos Dimas or Christos Papandreou.

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    Konstantinos Dimas and Christos Papandreou have contributed equally to this work.

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    Fig. S1

    Growth of MM cells in medium containing 0.5 % or 5 % serum. Growth curves obtained for RPMI-8226 (a) and NCI-H929 (b) cell lines in medium supplemented with 0.5 % or 5 % FBS. Cell growth was determined by MTT assay at 24, 48 and 72 h. Results were expressed as the mean ± SD from two independent experiments each performed in triplicate. (TIFF 115 kb)

    Fig. S2

    NEP cellular expression and activity in MM cell lines. (a) Western blot analysis of NEP expression in RPMI-8226 (left) and NCI-H929 cells (right). b-Actin is used as loading control. (b) NEP-specific activity (pmoles/μg/min) in RPMI-8226 (left) and NCI-H929 cells (right). LNCaP cell lysates were used as positive controls. Each point represents a mean ± SD of two independent experiments carried out in triplicate. (TIFF 154 kb)

    Fig. S3

    ETAR receptor is not involved in developing BTZ resistance. NCI-H929 (a) and RPMI-8226 (b) cell lines were treated in the absence or presence of ETAR antagonist (BQ123, 0.1 μM for 30 min), ET-1 (100 nM for 48 h) and BTZ (2 nM for 24 h) and cell proliferation analyzed by MTT assay. Incubation with medium served as control. Data represent mean values ± SD of two independent experiments each one performed in triplicate are indicated. P < 0.05; *vs CTL, #vs BTZ or BQ788, **vs ET-1 + BTZ, ##vs ET-1. (TIFF 219 kb)

    Fig. S4

    ETBR blockade potentiates the BTZ-mediated inhibition of myeloma cell proliferation and proteasome 20S activity. RPMI-8226 cells were either untreated (control) or treated with 0.1 μM ETBR antagonist, 100 nM ET-1 and 5 nM BTZ (IC50 of RPMI-8226 cells) as described in Materials and Methods. Cell proliferation (a) and levels of proteasome activity (b) were determined by MTT assay and proteasomal activity assay, respectively. Results were expressed as the mean ± SD from two independent experiments each one performed in at least duplicate. P < 0.05; *vs CTL, #vs BTZ or BQ788, **vs ET-1 + BTZ, ##vs ET-1. (TIFF 56 kb)

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    Vaiou, M., Pangou, E., Liakos, P. et al. Endothelin-1 (ET-1) induces resistance to bortezomib in human multiple myeloma cells via a pathway involving the ETB receptor and upregulation of proteasomal activity. J Cancer Res Clin Oncol 142, 2141–2158 (2016). https://doi.org/10.1007/s00432-016-2216-2

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