Induction of endoplasmic reticulum stress is associated with the anti-tumor activity of monepantel across cancer types.
Cancer Med
; 12(12): 13522-13537, 2023 06.
Article
em En
| MEDLINE
| ID: mdl-37148543
ABSTRACT
BACKGROUND:
Monepantel is an anti-helminthic drug that also has anti-cancer properties. Despite several studies over the years, the molecular target of monepantel in mammalian cells is still unknown, and its mechanism-of-action is not fully understood, though effects on cell cycle, mTOR signalling and autophagy have been implicated.METHODS:
Viability assays were performed on >20 solid cancer cell cells, and apoptosis assays were performed on a subset of these, including 3D cultures. Genetic deletion of BAX/BAK and ATG were used to establish roles of apoptosis and autophagy in killing activity. RNA-sequencing was performed on four cell lines after monepantel treatment, and differentially regulated genes were confirmed by Western blotting.RESULTS:
We showed that monepantel has anti-proliferative activity on a broad range of cancer cell lines. In some, this was associated with induction of apoptosis which was confirmed using a BAX/BAK-deficient cell line. However, proliferation is still inhibited in these cells following monepantel treatment, indicating cell-cycle disruption as the major anti-cancer effect. Previous studies have also indicated autophagic cell death occurs following monepantel treatment. We showed autophagy induction in multiple cell lines; however, deletion of a key autophagy regulator ATG7 had minimal impact on monepantel's anti-proliferative activity, suggesting autophagy is associated with, but not required for its anti-tumour effects. Transcriptomic analysis of four cell lines treated with monepantel revealed downregulation of many genes involved in the cell cycle, and upregulation of genes linked to ATF4-mediated ER stress responses, especially those involved in amino-acid metabolism and protein synthesis.CONCLUSIONS:
As these outcomes are all associated with mTOR signalling, cell cycle and autophagy, we now provide a likely triggering mechanism for the anti-cancer activity of monepantel.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estresse do Retículo Endoplasmático
/
Neoplasias
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article