Cathepsin K regulates localization and secretion of Tartrate-Resistant Acid Phosphatase (TRAP) in TRAP-overexpressing MDA-MB-231 breast cancer cells.
ACP5
Cancer
Cathepsin K
Intracellular trafficking
Proteolytic processing
Tartrate-resistant acid phosphatase
Journal
BMC molecular and cell biology
ISSN: 2661-8850
Titre abrégé: BMC Mol Cell Biol
Pays: England
ID NLM: 101741148
Informations de publication
Date de publication:
18 Mar 2020
18 Mar 2020
Historique:
received:
09
12
2019
accepted:
17
02
2020
entrez:
20
3
2020
pubmed:
20
3
2020
medline:
30
12
2020
Statut:
epublish
Résumé
Tartrate-resistant acid phosphatase (TRAP/ ACP5) belongs to the binuclear metallophosphatase family and is present in two isoforms. The primary translation product is an uncleaved TRAP 5a isoform with low phosphatase activity. TRAP 5a can be post-translationally processed to a cleaved TRAP 5b isoform with high phosphatase activity by e.g. cysteine proteinases, such as Cathepsin K (CtsK). The relevance of the phosphatase activity of TRAP 5b has been demonstrated for proliferation, migration and invasion of cancer cells. TRAP-overexpressing MDA-MB-231 breast cancer cells displayed higher levels of TRAP 5a and efficient processing of TRAP 5a to TRAP 5b protein, but no changes in levels of CtsK when compared to mock-transfected cells. In TRAP-overexpressing cells colocalization of TRAP 5a and proCtsK was augmented, providing a plausible mechanism for generation of TRAP 5b. CtsK expression has been associated with cancer progression and has been pharmacologically targeted in several clinical studies. In the current study, CtsK inhibition with MK-0822/Odanacatib did not abrogate the formation of TRAP 5b, but reversibly increased the intracellular levels of a N-terminal fragment of TRAP 5b and reduced secretion of TRAP 5a reversibly. However, MK-0822 treatment neither altered intracellular TRAP activity nor TRAP-dependent cell migration, suggesting involvement of additional proteases in proteolytic processing of TRAP 5a. Notwithstanding, CtsK was shown to be colocalized with TRAP and to be involved in the regulation of secretion of TRAP 5a in a breast cancer cell line, while it still was not essential for processing of TRAP 5a to TRAP 5b isoform. In cancer cells multiple proteases are involved in cleaving TRAP 5a to high-activity phosphatase TRAP 5b. However, CtsK-inhibiting treatment was able to reduce secretion TRAP 5a from TRAP-overexpressing cancer cells.
Sections du résumé
BACKGROUND
BACKGROUND
Tartrate-resistant acid phosphatase (TRAP/ ACP5) belongs to the binuclear metallophosphatase family and is present in two isoforms. The primary translation product is an uncleaved TRAP 5a isoform with low phosphatase activity. TRAP 5a can be post-translationally processed to a cleaved TRAP 5b isoform with high phosphatase activity by e.g. cysteine proteinases, such as Cathepsin K (CtsK). The relevance of the phosphatase activity of TRAP 5b has been demonstrated for proliferation, migration and invasion of cancer cells. TRAP-overexpressing MDA-MB-231 breast cancer cells displayed higher levels of TRAP 5a and efficient processing of TRAP 5a to TRAP 5b protein, but no changes in levels of CtsK when compared to mock-transfected cells. In TRAP-overexpressing cells colocalization of TRAP 5a and proCtsK was augmented, providing a plausible mechanism for generation of TRAP 5b. CtsK expression has been associated with cancer progression and has been pharmacologically targeted in several clinical studies.
RESULTS
RESULTS
In the current study, CtsK inhibition with MK-0822/Odanacatib did not abrogate the formation of TRAP 5b, but reversibly increased the intracellular levels of a N-terminal fragment of TRAP 5b and reduced secretion of TRAP 5a reversibly. However, MK-0822 treatment neither altered intracellular TRAP activity nor TRAP-dependent cell migration, suggesting involvement of additional proteases in proteolytic processing of TRAP 5a. Notwithstanding, CtsK was shown to be colocalized with TRAP and to be involved in the regulation of secretion of TRAP 5a in a breast cancer cell line, while it still was not essential for processing of TRAP 5a to TRAP 5b isoform.
CONCLUSION
CONCLUSIONS
In cancer cells multiple proteases are involved in cleaving TRAP 5a to high-activity phosphatase TRAP 5b. However, CtsK-inhibiting treatment was able to reduce secretion TRAP 5a from TRAP-overexpressing cancer cells.
Identifiants
pubmed: 32188406
doi: 10.1186/s12860-020-00253-6
pii: 10.1186/s12860-020-00253-6
pmc: PMC7081696
doi:
Substances chimiques
ACP5 protein, human
EC 3.1.3.2
Tartrate-Resistant Acid Phosphatase
EC 3.1.3.2
CTSK protein, human
EC 3.4.22.38
Cathepsin K
EC 3.4.22.38
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
15Subventions
Organisme : Vetenskapsrådet
ID : #2017-01083
Organisme : Vetenskapsrådet
ID : K2015-99X-10363-23-4
Organisme : Cancerfonden
ID : 2016
Organisme : Cancer and Allergy Foundation
ID : 2017
Organisme : Jane ja Aatos Erkon Säätiö
ID : 2017
Organisme : Loo och Hans Ostermans Stiftelse för Medicinsk Forskning
ID : 2018
Organisme : Maud Kuistilan Muistosäätiö
ID : 2017
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