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Apoptosis

, Volume 21, Issue 12, pp 1422–1437 | Cite as

Targeted knockdown of DJ-1 induces multiple myeloma cell death via KLF6 upregulation

  • Prahlad V. Raninga
  • Giovanna Di Trapani
  • Slavica Vuckovic
  • Kathryn F. TonissenEmail author
Article

Abstract

Multiple myeloma (MM) is an incurable plasma B cell malignancy. Despite recent advancements in anti-MM therapies, development of drug resistance remains a major clinical hurdle. DJ-1, a Parkinson’s disease-associated protein, is upregulated in many cancers and its knockdown suppresses tumor growth and overcomes chemoresistance. However, the role of DJ-1 in MM remains unknown. Using gene expression databases we found increased DJ-1 expression in MM patient cells, which correlated with shorter overall survival and poor prognosis in MM patients. Targeted DJ-1 knockdown using siRNAs induced necroptosis in myeloma cells. We found that Krüppel-like factor 6 (KLF6) is expressed at lower levels in myeloma cells compared to PBMCs, and DJ-1 knockdown increased KLF6 expression in myeloma cells. Targeted knockdown of KLF6 expression in DJ-1 knockdown myeloma cells rescued these cells from undergoing cell death. Higher DJ-1 levels were observed in bortezomib-resistant myeloma cells compared to parent cells, and siRNA-mediated DJ-1 knockdown reversed bortezomib resistance. DJ-1 knockdown increased KLF6 expression in bortezomib-resistant myeloma cells, and subsequent siRNA-mediated KLF6 knockdown rescued bortezomib-resistant myeloma cells from undergoing cell death. We also demonstrated that specific siRNA-mediated DJ-1 knockdown reduced myeloma cell growth under a hypoxic microenvironment. DJ-1 knockdown reduced the expression of HIF-1α and its target genes in hypoxic-myeloma cells, and overcame hypoxia-induced bortezomib resistance. Our findings demonstrate that elevated DJ-1 levels correlate with myeloma cell survival and acquisition of bortezomib resistance. Thus, we propose that inhibiting DJ-1 may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM patients.

Keywords

DJ-1 Drug resistance Hypoxia KLF6 Necroptosis Multiple myeloma 

Abbreviations

ANOVA

Analysis of variance

BM

Bone marrow

Btz

Bortezomib

Ct

Cycle of threshold

CuZnSOD

Copper–zinc superoxide dismutase

ECL

Enhanced chemiluminescence

GEP

Gene expression profile

HIF-1α

Hypoxia-inducible factor-1 alpha

HR

Hazard ratio

Hx

Hypoxia

KLF6

Krüppel-like factor 6

LDHA

Lactate dehydrogenase A

MM

Multiple myeloma

NF-кβ

Nuclear factor kappa beta

Nrf2

Nuclear factor-E2-related factor 2

Nrx

Normoxia

PBMCs

Peripheral blood mononuclear cells

PD

Parkinson’s disease

PI3K

Phosphoinositide-3 kinase

PMA

Phorbol 12-myristate 13-acetate

PTEN

Phosphatase and tensin homolog

RPL32

Ribosomal Protein L32

RT-qPCR

Reverse transcriptase-quantitative PCR

SEM

Standard error of the mean

siRNA

Small interfering RNA

SMAC

Second mitochondrial activator of apoptosis

TRAIL

Tumor necrosis factor-related apoptosis-inducing ligand

Trx1

Thioredoxin 1

TrxR1

Thioredoxin reductase 1

TT2

Total therapy 2

TT3

Total therapy 3

U266-BR

Bortezomib-resistant U266 cells

VEGF

Vascular endothelial growth factor

Notes

Acknowledgments

We thank A/Prof. Stephen Wood (Eskitis Institute, Brisbane, Australia) and his lab members for their help in setting up transfection experiments, Prof. George Mellick (Eskitis Institute, Brisbane, Australia) for collecting the blood samples from healthy individuals, and Tony Blick (Queensland University of Technology, Australia) for technical advice.

Funding

This research was supported by a Griffith University Post-graduate Research Scholarship and a Griffith University International Post-graduate Scholarship (to P. R). This research was also supported by the Cancer Therapeutics CRC (Australia) PhD Top-Up Scholarship to P. R. We also thank Griffith University for providing additional financial support to carry out this research.

Compliance with ethical standards

The experiments performed in this study comply with the current laws of Australia.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10495_2016_1303_MOESM1_ESM.tif (71 kb)
Figure S1: siRNA-induced knockdown of KLF6 in PBMCs. PBMCs (2 × 106 cells) were transfected with 50 nmol/l of either control or KLF6-specific siRNA. KLF6 mRNA levels were analyzed 48 h post-transfection by RT-qPCR. KLF6 mRNA levels were normalized against RPL32. Values indicated mean ± SEM (n = 3). Unpaired Student’s t test was employed. *P < 0.05 (TIF 70 KB)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Prahlad V. Raninga
    • 1
    • 2
  • Giovanna Di Trapani
    • 1
  • Slavica Vuckovic
    • 3
    • 4
  • Kathryn F. Tonissen
    • 1
    • 2
    Email author
  1. 1.School of Natural SciencesGriffith UniversityBrisbaneAustralia
  2. 2.Eskitis Institute for Drug DiscoveryGriffith UniversityNathanAustralia
  3. 3.QIMR Berghofer Medical Research InstituteHerstonAustralia
  4. 4.School of MedicineUniversity of QueenslandHerstonAustralia

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