Streptonigrin Mitigates Lung Cancer-induced Cachexia by Suppressing TCF4/TWIST1-induced PTHLH Expression.
Anticancer Res
; 43(3): 1149-1157, 2023 Mar.
Article
em En
| MEDLINE
| ID: mdl-36854496
ABSTRACT
BACKGROUND/AIM:
Cachexia - a wasting disorder of adipose and skeletal muscle tissue - is the most common driver of poor prognosis in patients with advanced lung cancer. Parathyroid hormone-like hormone (PTHLH) is potentially a critical factor in cancer-associated cachexia. We previously showed that streptonigrin - an aminoquinone with antitumor effects - inhibited the interaction between TCF4 and TWIST1. This study aimed to determine the anti-cachectic performance of streptonigrin in lung cancer. MATERIALS ANDMETHODS:
We assessed the effect of streptonigrin on the interaction of TCF4 and TWIST1 using co-immunoprecipitation and a mammalian-two hybrid luciferase assay, which was confirmed by an in vitro GST pull-down assay using recombinant bHLH domain-containing TCF4 and TWIST1. We assessed the anti-cachectic effect of streptonigrin in vivo using an LLC1 cell-induced tumour-bearing mouse model. Changes in the degree of skeletal muscle and adipose tissue wasting were determined by measuring the weights of gastrocnemius and epidydimal white adipose tissue.RESULTS:
Streptonigrin was found to inhibit the interaction of TCF4 with TWIST1 in a dose-dependent manner. The in vitro GST pull-down assay revealed that streptonigrin directly inhibited the interaction between TCF4 and TWIST1. The expression of PTHLH mRNA, which is transcriptionally regulated by the TCF4/TWIST1 complex in response to TGF-ß1 signalling, was decreased in streptonigrin-treated lung cancer cells. Streptonigrin significantly decreased the expression of proteolysis-related genes in skeletal muscle and browning-related genes in white adipose tissues of LLC1-induced tumour-bearing mice.CONCLUSION:
Streptonigrin exerts potent therapeutic effects on lung cancer-induced cachexia by suppressing TCF4/TWIST1-mediated PTHLH expression.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Caquexia
/
Neoplasias Pulmonares
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Anticancer Res
Ano de publicação:
2023
Tipo de documento:
Article