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2016 ; 7
(1
): 831-44
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Auranofin is a potent suppressor of osteosarcoma metastasis
#MMPMID26573231
Topkas E
; Cai N
; Cumming A
; Hazar-Rethinam M
; Gannon OM
; Burgess M
; Saunders NA
; Endo-Munoz L
Oncotarget
2016[Jan]; 7
(1
): 831-44
PMID26573231
show ga
Osteosarcoma (OS) accounts for 56% of malignant bone cancers in children and
adolescents. Patients with localized disease rarely develop metastasis; however,
pulmonary metastasis occurs in approximately 50% of patients and leads to a
5-year survival rate of only 10-20%. Therefore, identifying the genes and
pathways involved in metastasis, as new therapeutic targets, is crucial to
improve long-term survival of OS patients. Novel markers that define metastatic
OS were identified using comparative transcriptomic analyses of two highly
metastatic (C1 and C6) and two poorly metastatic clonal variants (C4 and C5)
isolated from the metastatic OS cell line, KHOS. Using this approach, we
determined that the metastatic phenotype correlated with overexpression of
thioredoxin reductase 2 (TXNRD2) or vascular endothelial growth factor (VEGF).
Validation in patient biopsies confirmed TXNRD2 and VEGF targets were highly
expressed in 29-42% of metastatic OS patient biopsies, with no detectable
expression in non-malignant bone or samples from OS patients with localised
disease. Auranofin (AF) was used to selectively target and inhibit thioredoxin
reductase (TrxR). At low doses, AF was able to inhibit TrxR activity without a
significant effect on cell viability whereas at higher doses, AF could induce
ROS-dependent apoptosis. AF treatment, in vivo, significantly reduced the
development of pulmonary metastasis and we provide evidence that this effect may
be due to an AF-dependent increase in cellular ROS. Thus, TXNRD2 may represent a
novel druggable target that could be deployed to reduce the development of fatal
pulmonary metastases in patients with OS.
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