Metformin Promotes Beclin1-Dependent Autophagy to Inhibit the Progression of Gastric Cancer.
AMPK-mTOR signalling pathway
GC
autophagy
beclin1
gastric cancer
metformin
Journal
OncoTargets and therapy
ISSN: 1178-6930
Titre abrégé: Onco Targets Ther
Pays: New Zealand
ID NLM: 101514322
Informations de publication
Date de publication:
2020
2020
Historique:
received:
13
12
2019
accepted:
26
03
2020
entrez:
18
6
2020
pubmed:
18
6
2020
medline:
18
6
2020
Statut:
epublish
Résumé
Metformin is the first-line blood sugar control drug for type 2 diabetes, but recent epidemiological studies have shown that it inhibits the growth of a variety of tumours. However, few studies have examined metformin effects on gastric cancer (GC), and the anticancer mechanism has not been fully elucidated. We examined the inhibitory effect of metformin on GC cells by cell proliferation, migration and invasion assay. Transmission electron microscopy, confocal microscopy and Western blotting confirmed that metformin enhanced beclin1-dependent autophagy in gastric cancer cells. TCGA database and tissue chip analysis confirmed the differential expression of beclin1 in GC and adjacent tissues. Relevant functional tests verified the role of beclin1 as a tumour suppressor gene in GC. Western blotting, cell proliferation, cell migration and invasion were used to verify that metformin enhances autophagy in GC cells through the AMPK-mTOR signalling pathway. Xenograft tumour models were constructed to explore the inhibitory effect of metformin and the role of beclin1 as a suppressor on GC in vivo. In this study, we observed that metformin inhibits proliferation, migration and invasion of GC cells. Metformin could also promote beclin1-dependent autophagy in GC cells. We further discovered that beclin1 expression was downregulated in GC and that its low expression was associated with poor prognosis. Beclin1 acts as a tumour suppressor that inhibits the malignant phenotypes of GC cells in vitro and in vivo. Furthermore, we verified that metformin can upregulate beclin1-mediated autophagy to inhibit GC cells through the AMPK-mTOR signalling pathway. In summary, the results revealed the role of autophagy in metformin inhibition of gastric cancer and suggest that beclin1 may be a potential target for gastric cancer therapy.
Sections du résumé
BACKGROUND
BACKGROUND
Metformin is the first-line blood sugar control drug for type 2 diabetes, but recent epidemiological studies have shown that it inhibits the growth of a variety of tumours. However, few studies have examined metformin effects on gastric cancer (GC), and the anticancer mechanism has not been fully elucidated.
MATERIALS AND METHODS
METHODS
We examined the inhibitory effect of metformin on GC cells by cell proliferation, migration and invasion assay. Transmission electron microscopy, confocal microscopy and Western blotting confirmed that metformin enhanced beclin1-dependent autophagy in gastric cancer cells. TCGA database and tissue chip analysis confirmed the differential expression of beclin1 in GC and adjacent tissues. Relevant functional tests verified the role of beclin1 as a tumour suppressor gene in GC. Western blotting, cell proliferation, cell migration and invasion were used to verify that metformin enhances autophagy in GC cells through the AMPK-mTOR signalling pathway. Xenograft tumour models were constructed to explore the inhibitory effect of metformin and the role of beclin1 as a suppressor on GC in vivo.
RESULTS
RESULTS
In this study, we observed that metformin inhibits proliferation, migration and invasion of GC cells. Metformin could also promote beclin1-dependent autophagy in GC cells. We further discovered that beclin1 expression was downregulated in GC and that its low expression was associated with poor prognosis. Beclin1 acts as a tumour suppressor that inhibits the malignant phenotypes of GC cells in vitro and in vivo. Furthermore, we verified that metformin can upregulate beclin1-mediated autophagy to inhibit GC cells through the AMPK-mTOR signalling pathway.
CONCLUSION
CONCLUSIONS
In summary, the results revealed the role of autophagy in metformin inhibition of gastric cancer and suggest that beclin1 may be a potential target for gastric cancer therapy.
Identifiants
pubmed: 32547075
doi: 10.2147/OTT.S242298
pii: 242298
pmc: PMC7245468
doi:
Types de publication
Journal Article
Langues
eng
Pagination
4445-4455Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2020 Liu et al.
Déclaration de conflit d'intérêts
The authors report no conflicts of interest in this work.
Références
Clin Cancer Res. 2011 Feb 15;17(4):654-66
pubmed: 21325294
Am J Cancer Res. 2019 Oct 01;9(10):2170-2193
pubmed: 31720081
J Clin Med. 2020 Feb 05;9(2):
pubmed: 32033451
Mol Cancer Res. 2019 Apr;17(4):870-881
pubmed: 30655321
Cancer Biol Ther. 2011 Jan 15;11(2):169-76
pubmed: 21263212
Cell Metab. 2016 Oct 11;24(4):521-522
pubmed: 27732831
J Biol Chem. 2015 Mar 13;290(11):6986-93
pubmed: 25632961
EMBO Rep. 2001 Apr;2(4):330-5
pubmed: 11306555
Mol Biol Cell. 2008 Nov;19(11):4651-9
pubmed: 18768752
Mol Cancer. 2017 Jul 24;16(1):131
pubmed: 28738823
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
Hepatol Res. 2019 Apr;49(4):462-472
pubmed: 30565807
Int J Mol Sci. 2018 Nov 05;19(11):
pubmed: 30400561
J Exp Clin Cancer Res. 2019 Aug 27;38(1):376
pubmed: 31455378
Biomed Pharmacother. 2019 Jul;115:108892
pubmed: 31029889
Cancer Lett. 2019 Jul 10;454:215-223
pubmed: 30980867
Autophagy. 2016 Sep;12(9):1447-59
pubmed: 27304906
Diabetes Care. 2015 Jan;38(1):140-9
pubmed: 25538310
J Transl Med. 2015 Mar 15;13:92
pubmed: 25884210
Cell Res. 2014 Jan;24(1):24-41
pubmed: 24366339
Autophagy. 2016;12(1):1-222
pubmed: 26799652
Cell Death Differ. 2011 Apr;18(4):571-80
pubmed: 21311563
Carcinogenesis. 2019 Jul 4;40(5):669-679
pubmed: 30445633
Aging (Albany NY). 2016 Aug;8(8):1636-49
pubmed: 27587088
Oncogene. 2008 Dec;27 Suppl 1:S137-48
pubmed: 19641499
J Clin Invest. 2015 Jan;125(1):25-32
pubmed: 25654547
Mol Cancer Ther. 2011 Sep;10(9):1533-41
pubmed: 21878654
Pharmacol Res. 2016 Nov;113(Pt A):675-685
pubmed: 27720766
J Mol Endocrinol. 2017 Jan;58(1):15-23
pubmed: 27920093
Int J Endocrinol. 2019 Jan 10;2019:7570146
pubmed: 30774659
Cell Metab. 2017 Feb 7;25(2):463-471
pubmed: 28089566
Cancer Res. 2019 Sep 1;79(17):4360-4370
pubmed: 31292160
Cell Cycle. 2015;14(20):3331-9
pubmed: 26323019
EMBO J. 2000 Nov 1;19(21):5720-8
pubmed: 11060023