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2018 ; 52
(6
): 1841-1852
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S-phase kinase-associated protein 2 is involved in epithelial-mesenchymal
transition in methotrexate-resistant osteosarcoma cells
#MMPMID29620168
Ding L
; Wang C
; Cui Y
; Han X
; Zhou Y
; Bai J
; Li R
Int J Oncol
2018[Jun]; 52
(6
): 1841-1852
PMID29620168
show ga
Osteosarcoma (OS), a common worldwide primary aggressive bone malignancy, arises
from primitive transformed cells of mesenchymal origin and usually attacks
adolescents and young adults. Methotrexate (MTX) is the anti-folate drug used as
a pivotal chemotherapeutic agent in the treatment of OS. However, patients with
OS often develop drug resistance, leading to poor treatment outcomes. In the
present study, in order to explore the underlying mechanisms responsible for MTX
resistance, we established MTX?resistant OS cells using the U2OS and MG63 cell
lines and examined whether MTX?resistant OS cells underwent
epithelial-mesenchymal transition (EMT) by Transwell assay, wound healing assay,
MTT assay, RT-PCR and western blot analysis. We found that the viability of the
MTX?resistant cells remained relatively unaltered following further treatment
with MTX compared to the parental cells. The resistant cells appeared to possess
a mesenchymal phenotype, with an elongated and more spindle?like shape, and
acquired enhanced invasive, migratory and attachment abilities. The measurement
of EMT markers also supported EMT transition in the MTX?resistant OS cells. Our
result further demonstrated that the overexpression of S-phase kinase-associated
protein 2 (Skp2) was closely involved in the resistance of OS cells to MTX and in
the acquirement of EMT properties. Thus, the pharmacological inhibition of Skp2
may prove to be a novel therapeutic strategy with which to overcome drug
resistance in OS.