TGF-ß1 induced autophagy in cancer associated fibroblasts during hypoxia contributes EMT and glycolysis via MCT4 upregulation.
Exp Cell Res
; 417(1): 113195, 2022 08 01.
Article
em En
| MEDLINE
| ID: mdl-35561786
ABSTRACT
The Transforming growth factor-ß1 (TGF- ß1) in the tumor microenvironment (TME) is the major cytokine that acts as a mediator of tumor-stroma crosstalk, which in fact has a dual role in either promoting or suppressing tumor development. The cancer-associated fibroblasts (CAFs) are the major cell types in the TME, and the interaction with most of the epithelial cancers is the prime reason for cancer survival. However, the molecular mechanisms, associated with the TGF- ß1 induced tumor promotion through tumor-CAF crosstalk are not well understood. In the Reverse Warburg effect, CAFs feed the adjacent cancer cells by lactate produced during the aerobic glycolysis. We hypothesized that the monocarboxylate transporter, MCT4 which is implicated in lactate efflux from the CAFs, must be overexpressed in the CAFs. Contextually, to explore the role of TGF- ß1 in the hypoxia-induced autophagy in CAFs, we treated CoCl2 and external TGF- ß1 to the human dermal fibroblasts and L929 murine fibroblasts. We demonstrated that hypoxia accelerated the TGF- ß1 signaling and subsequent transformation of normal fibroblasts to CAFs. Moreover, we elucidated that synergistic induction of autophagy by hypoxia and TGF- ß1 upregulate the aerobic glycolysis and MCT4 expression in CAFs. Furthermore, we showed a positive correlation between glucose consumption and MCT4 expression in the CAFs. Autophagy was also found to be involved in the EMT in hypoxic CAFs. Collectively, these findings reveal the unappreciated role of autophagy in TME, which enhances the CAF transformation and that promotes tumor migration and metastasis via the reverse Warburg effect.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autofagia
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Transportadores de Ácidos Monocarboxílicos
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Fator de Crescimento Transformador beta1
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Fibroblastos Associados a Câncer
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Proteínas Musculares
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Neoplasias
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Exp Cell Res
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Índia