A combination of AZD5363 and FH5363 induces lethal autophagy in transformed hepatocytes.
Adenylate Kinase
/ metabolism
Autophagy
/ drug effects
Biomarkers
/ metabolism
Cell Line, Transformed
Cell Nucleus
/ drug effects
Cell Proliferation
/ drug effects
Dynamins
/ metabolism
Hepatocytes
/ cytology
Humans
Nuclear Proteins
/ metabolism
Protein Transport
/ drug effects
Proto-Oncogene Proteins c-mdm2
/ metabolism
Pyrimidines
/ pharmacology
Pyrroles
/ pharmacology
Signal Transduction
/ drug effects
Subcellular Fractions
/ metabolism
Sulfonamides
/ pharmacology
TOR Serine-Threonine Kinases
/ metabolism
Tumor Suppressor Protein p53
/ metabolism
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
17 07 2020
17 07 2020
Historique:
received:
22
04
2020
accepted:
29
06
2020
revised:
23
06
2020
entrez:
19
7
2020
pubmed:
19
7
2020
medline:
25
3
2021
Statut:
epublish
Résumé
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. High Akt activation and aberrant β-catenin expression contribute to HCC cell proliferation, stem cell generation, and metastasis. Several signaling pathway-specific inhibitors are in clinical trials and display different efficacies against HCC. In this study, we observed that a β-catenin inhibitor (FH535) displays antiproliferative effect on transformed human hepatocytes (THH). A combination treatment of these cells with FH535 and Akt inhibitor (AZD5363) exerted a stronger effect on cell death. Treatment of THH with AZD5363 and FH535 inhibited cell-cycle progression, enhanced autophagy marker protein expression, and autophagy-associated death, while FH535 treatment alone induced apoptosis. The use of chloroquine or z-VAD further verified these observations. Autophagy flux was evident from lowering marker proteins LAMP2, LAPTM4B, and autophagic protein expression by confocal microscopy using mCherry-EGFP-LC3 reporter construct. A combination treatment with AZD5363 and FH535 enhanced p53 expression, by modulating MDM2 activation; however, AZD5363 treatment alone restricted p53 to the nucleus by inhibiting dynamin-related protein activation. Nuclear p53 plays a crucial role for activation of autophagy by regulating the AMPK-mTOR-ULK1 pathway. Hep3B cells with null p53 did not modulate autophagy-dependent death from combination treatment. Together, our results strongly suggested that a combination treatment of Akt and β-catenin inhibitors exhibits efficient therapeutic potential for HCC.
Identifiants
pubmed: 32681102
doi: 10.1038/s41419-020-02741-1
pii: 10.1038/s41419-020-02741-1
pmc: PMC7367822
doi:
Substances chimiques
Biomarkers
0
FH535
0
Nuclear Proteins
0
Pyrimidines
0
Pyrroles
0
SESN2 protein, human
0
Sulfonamides
0
Tumor Suppressor Protein p53
0
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
TOR Serine-Threonine Kinases
EC 2.7.11.1
Adenylate Kinase
EC 2.7.4.3
Dynamins
EC 3.6.5.5
capivasertib
WFR23M21IE
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
540Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK113645
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK081817
Pays : United States
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