Down-regulation of dual-specificity phosphatase 6, a negative regulator of oncogenic ERK signaling, by ACA-28 induces apoptosis in NIH/3T3 cells overexpressing HER2/ErbB2.
ACA-28
ERK MAPK
apoptosis
cancer treatment
dual-specificity phosphatase
proteasome-dependent degradation
Journal
Genes to cells : devoted to molecular & cellular mechanisms
ISSN: 1365-2443
Titre abrégé: Genes Cells
Pays: England
ID NLM: 9607379
Informations de publication
Date de publication:
Feb 2021
Feb 2021
Historique:
received:
05
10
2020
revised:
20
11
2020
accepted:
21
11
2020
pubmed:
30
11
2020
medline:
16
7
2021
entrez:
29
11
2020
Statut:
ppublish
Résumé
Dual-specificity phosphatase 6 (DUSP6) is a key negative feedback regulator of the member of the RAS-ERK MAPK signaling pathway that is associated with cellular proliferation and differentiation. Deterioration of DUSP6 expression could therefore result in deregulated growth activity. We have previously discovered ACA-28, a novel anticancer compound with a unique property to stimulate ERK phosphorylation and induce apoptosis in ERK-active melanoma cells. However, the mechanism of cancer cell-specific-apoptosis by ACA-28 remains obscure. Here, we investigated the involvement of DUSP6 in the mechanisms of the ACA-28-mediated apoptosis by using the NIH/3T3 cells overexpressing HER2/ErbB2 (A4-15 cells), as A4-15 exhibited higher ERK phosphorylation and are more susceptible to ACA-28 than NIH/3T3. We showed that A4-15 exhibited high DUSP6 protein levels, which require ERK activation. Notably, the silencing of the DUDSP6 gene by siRNA inhibited proliferation and induced apoptosis in A4-15, but not in NIH/3T3, indicating that A4-15 requires high DUSP6 expression for growth. Importantly, ACA-28 preferentially down-regulated the DUSP6 protein and proliferation in A4-15 via the proteasome, while it stimulated ERK phosphorylation. Collectively, the up-regulation of DUSP6 may exert a growth-promoting role in cancer cells overexpressing HER2. DUSP6 down-regulation in ERK-active cancer cells might have the potential as a novel cancer measure.
Substances chimiques
ACA-28 cpd
0
Benzyl Alcohols
0
Receptor, ErbB-2
EC 2.7.10.1
Dual Specificity Phosphatase 6
EC 3.1.3.48
Dusp6 protein, mouse
EC 3.1.3.48
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
109-116Informations de copyright
© 2020 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.
Références
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