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2017 ; 17
(1
): 650
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Tartrate-resistant acid phosphatase (TRAP/ACP5) promotes metastasis-related
properties via TGF?2/T?R and CD44 in MDA-MB-231 breast cancer cells
#MMPMID28915803
Reithmeier A
; Panizza E
; Krumpel M
; Orre LM
; Branca RMM
; Lehtiö J
; Ek-Rylander B
; Andersson G
BMC Cancer
2017[Sep]; 17
(1
): 650
PMID28915803
show ga
BACKGROUND: Tartrate-resistant acid phosphatase (TRAP/ACP5), a metalloenzyme that
is characteristic for its expression in activated osteoclasts and in macrophages,
has recently gained considerable focus as a driver of metastasis and was
associated with clinically relevant parameters of cancer progression and cancer
aggressiveness. METHODS: MDA-MB-231 breast cancer cells with different TRAP
expression levels (overexpression and knockdown) were generated and characterized
for protein expression and activity levels. Functional cell experiments, such as
proliferation, migration and invasion assays were performed as well as global
phosphoproteomic and proteomic analysis was conducted to connect molecular
perturbations to the phenotypic changes. RESULTS: We identified an association
between metastasis-related properties of TRAP-overexpressing MDA-MB-231 breast
cancer cells and a TRAP-dependent regulation of Transforming growth factor (TGF?)
pathway proteins and Cluster of differentiation 44 (CD44). Overexpression of TRAP
increased anchorage-independent and anchorage-dependent cell growth and
proliferation, induced a more elongated cellular morphology and promoted cell
migration and invasion. Migration was increased in the presence of the
extracellular matrix (ECM) proteins osteopontin and fibronectin and the basement
membrane proteins collagen IV and laminin I. TRAP-induced properties were
reverted upon shRNA-mediated knockdown of TRAP or treatment with the small
molecule TRAP inhibitor 5-PNA. Global phosphoproteomics and proteomics analyses
identified possible substrates of TRAP phosphatase activity or signaling
intermediates and outlined a TRAP-dependent regulation of proteins involved in
cell adhesion and ECM organization. Upregulation of TGF? isoform 2 (TGF?2), TGF?
receptor type 1 (T?R1) and Mothers against decapentaplegic homolog 2 (SMAD2), as
well as increased intracellular phosphorylation of CD44 were identified upon TRAP
perturbation. Functional antibody-mediated blocking and chemical inhibition
demonstrated that TRAP-dependent migration and proliferation is regulated via
TGF?2/T?R, whereas proliferation beyond basal levels is regulated through CD44.
CONCLUSION: Altogether, TRAP promotes metastasis-related cell properties in
MDA-MB-231 breast cancer cells via TGF?2/T?R and CD44, thereby identifying a
potential signaling mechanism associated to TRAP action in breast cancer cells.
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