The Major Heat Shock Proteins, Hsp70 and Hsp90, in 2-Methoxyestradiol-Mediated Osteosarcoma Cell Death Model.
2-Methoxyestradiol
/ pharmacology
Animals
Antibiotics, Antineoplastic
/ pharmacology
Antineoplastic Agents
/ pharmacology
Benzoquinones
/ pharmacology
Bone Neoplasms
/ drug therapy
Drug Interactions
HSP70 Heat-Shock Proteins
/ antagonists & inhibitors
HSP90 Heat-Shock Proteins
/ antagonists & inhibitors
Humans
Lactams, Macrocyclic
/ pharmacology
Models, Biological
Osteosarcoma
/ drug therapy
2-methoxyestradiol
geldanamycin
neuronal nitric oxide synthase
osteosarcoma
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
17 Jan 2020
17 Jan 2020
Historique:
received:
19
11
2019
revised:
27
12
2019
accepted:
14
01
2020
entrez:
23
1
2020
pubmed:
23
1
2020
medline:
24
10
2020
Statut:
epublish
Résumé
2-Methoxyestradiol is one of the natural 17β-estradiol derivatives and a potential novel anticancer agent currently being under evaluation in advanced phases of clinical trials. However, the mechanism of anticancer action of 2-methoxyestradiol has not been yet fully established. In our previous studies we have demonstrated that 2-methoxyestradiol selectively induces the expression and nuclear translocation of neuronal nitric oxide synthase in osteosarcoma 143B cells. Heat shock proteins (Hsps) are factors involved in the regulation of expression and activity of nitric oxide synthases. Herein, we chose osteosarcoma cell lines differed in metastatic potential, metastatic 143B and highly metastatic MG63.2 cells, in order to further investigate the anticancer mechanism of 2-methoxyestradiol. The current study aimed to determine the role of major heat shock proteins, Hsp90 and Hsp70 in 2-methoxyestradiol-induced osteosarcoma cell death. We focused on the implication of Hsp90 and Hsp70 in control under expression of neuronal nitric oxide synthase, localization of the enzyme, and further generation of nitro-oxidative stress. To give the insight into the role of Hsp90 in regulation of anticancer efficacy of 2-methoxyestradiol, we used geldanamycin as a potent Hsp90 inhibitor. Herein, we evidenced that inhibition of Hsp90 controls the protein expression of 2-methoxyestradiol-induced neuronal nitric oxide synthase and inhibits enzyme nuclear translocation. We propose that decreased level of neuronal nitric oxide synthase protein after a combined treatment with 2-methoxyestradiol and geldanamycin is directly associated with the accompanying upregulation of Hsp70 and downregulation of Hsp90. This interaction resulted in abrogation of anticancer efficacy of 2-methoxyestradiol by geldanamycin.
Identifiants
pubmed: 31963524
pii: ijms21020616
doi: 10.3390/ijms21020616
pmc: PMC7014403
pii:
doi:
Substances chimiques
Antibiotics, Antineoplastic
0
Antineoplastic Agents
0
Benzoquinones
0
HSP70 Heat-Shock Proteins
0
HSP90 Heat-Shock Proteins
0
Lactams, Macrocyclic
0
2-Methoxyestradiol
6I2QW73SR5
geldanamycin
Z3K3VJ16KU
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministerstwo Nauki i Szkolnictwa Wyższego
ID : No IP 2015 022074
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