Saucerneol attenuates nasopharyngeal carcinoma cells proliferation and metastasis through selectively targeting Grp94.
Animals
Cell Line, Tumor
Cell Movement
Cell Proliferation
Furans
/ pharmacology
Gene Expression Regulation, Neoplastic
HSP70 Heat-Shock Proteins
/ metabolism
Humans
Lignans
/ pharmacology
Membrane Proteins
/ metabolism
Mice
Mice, Nude
Nasopharyngeal Carcinoma
/ metabolism
Nasopharyngeal Neoplasms
/ drug therapy
Phosphatidylinositol 3-Kinases
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
TOR Serine-Threonine Kinases
/ metabolism
Grp94
Hsp90
Nasopharyngeal carcinoma
PI3K/AKT/mTOR
Saucerneol
Journal
Phytomedicine : international journal of phytotherapy and phytopharmacology
ISSN: 1618-095X
Titre abrégé: Phytomedicine
Pays: Germany
ID NLM: 9438794
Informations de publication
Date de publication:
Jul 2022
Jul 2022
Historique:
received:
12
11
2021
revised:
19
04
2022
accepted:
24
04
2022
pubmed:
4
5
2022
medline:
19
5
2022
entrez:
3
5
2022
Statut:
ppublish
Résumé
Nasopharyngeal carcinoma (NPC) is highly prevalent in southern China. The remote metastasis of advanced NPC requires chemotherapeutic treatments to reduce the mortality. Our previous work revealed that saucerneol (SN) showed cytotoxicity against several nasopharyngeal carcinoma (NPC) cells. This work aims to investigate the effect of SN in NPC growth and exploring the mechanism of action. Applying in vivo study, in vitro study and in silico study to indicate the mechanism of SN in inhibiting NPC growth. Saucerneol (SN) toxicity was measured with MTT assay. NPC proliferation was measured with EdU and colony formation assays, cell cycle was detected with flow cytometry. NPC migration and invasion were measured with scratch assay and matrigel transwell method. Further, human NPC xenograft tumor models were established in nude mice to evaluate the therapeutic efficacy of SN in vivo. Toxicological analysis was performed on H&E staining and IHC. Quantitative real-time PCR and Western blot analyses were used to evaluate the expression levels of key molecules in PI3K/AKT/mTOR, MAPK, NF-κB, and HIF-1α signal pathways. Target predicting was conducted using computational method, and target identification was carried out by ATPase assay and TSA. SN, a potent NPC inhibitor that was previously isolated from Saururus chinensis in our lab, is proven to inhibit the proliferation and metastasis of HONE1 cell lines and inhibit the growth of human NPC xenografts in nude mice. Moreover, we further articulate the molecular mechanism of action for SN and, reveal that SN promotes the expression of cell cycle-dependent kinase inhibitory protein p21 Waf1/Cip1 through targeting Grp94 and then inhibiting PI3K/AKT signaling pathway as well as up-regulating p53 to disrupt the progression of HONE1 cells. SN significantly inhibits NPC cells proliferation and metastasis in vitro and in vivo via selectively inhibit Grp94 and then blocking PI3K/AKT/mTOR/HIF-1α signaling pathway. This study firstly provides a novel selective Grp94 inhibitor as a NPC candidate.
Sections du résumé
BACKGROUND
BACKGROUND
Nasopharyngeal carcinoma (NPC) is highly prevalent in southern China. The remote metastasis of advanced NPC requires chemotherapeutic treatments to reduce the mortality. Our previous work revealed that saucerneol (SN) showed cytotoxicity against several nasopharyngeal carcinoma (NPC) cells. This work aims to investigate the effect of SN in NPC growth and exploring the mechanism of action.
STUDY DESIGN
METHODS
Applying in vivo study, in vitro study and in silico study to indicate the mechanism of SN in inhibiting NPC growth.
METHODS
METHODS
Saucerneol (SN) toxicity was measured with MTT assay. NPC proliferation was measured with EdU and colony formation assays, cell cycle was detected with flow cytometry. NPC migration and invasion were measured with scratch assay and matrigel transwell method. Further, human NPC xenograft tumor models were established in nude mice to evaluate the therapeutic efficacy of SN in vivo. Toxicological analysis was performed on H&E staining and IHC. Quantitative real-time PCR and Western blot analyses were used to evaluate the expression levels of key molecules in PI3K/AKT/mTOR, MAPK, NF-κB, and HIF-1α signal pathways. Target predicting was conducted using computational method, and target identification was carried out by ATPase assay and TSA.
RESULTS
RESULTS
SN, a potent NPC inhibitor that was previously isolated from Saururus chinensis in our lab, is proven to inhibit the proliferation and metastasis of HONE1 cell lines and inhibit the growth of human NPC xenografts in nude mice. Moreover, we further articulate the molecular mechanism of action for SN and, reveal that SN promotes the expression of cell cycle-dependent kinase inhibitory protein p21 Waf1/Cip1 through targeting Grp94 and then inhibiting PI3K/AKT signaling pathway as well as up-regulating p53 to disrupt the progression of HONE1 cells.
CONCLUSION
CONCLUSIONS
SN significantly inhibits NPC cells proliferation and metastasis in vitro and in vivo via selectively inhibit Grp94 and then blocking PI3K/AKT/mTOR/HIF-1α signaling pathway. This study firstly provides a novel selective Grp94 inhibitor as a NPC candidate.
Identifiants
pubmed: 35504052
pii: S0944-7113(22)00212-4
doi: 10.1016/j.phymed.2022.154133
pii:
doi:
Substances chimiques
Furans
0
HSP70 Heat-Shock Proteins
0
Lignans
0
Membrane Proteins
0
glucose-regulated proteins
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
154133Informations de copyright
Copyright © 2022. Published by Elsevier GmbH.