Prolyl hydroxylase 2 inhibits glycolytic activity in colorectal cancer via the NFκB signaling pathway.
Int J Oncol
; 64(1)2024 01.
Article
em En
| MEDLINE
| ID: mdl-37975227
ABSTRACT
A variety of malignancies preferentially meet energy demands through the glycolytic pathway. Hypoxiainduced cancer cell adaptations are essential for tumor development. However, in cancerous glycolysis, the functional importance and underlying molecular mechanism of prolyl hydroxylase domain protein 2 (PHD2) have not been fully elucidated. Gain and lossoffunction assays were conducted to evaluate PHD2 functions in colon cancer cells. Glucose uptake, lactate production and intracellular adenosine5'triphosphate/adenosine diphosphate ratio were measured to determine glycolytic activities. Protein and gene expression levels were measured by western blot analysis and reverse transcriptionquantitative PCR, respectively. The human colon cancer xenograft model was used to confirm the role of PHD2 in tumor progression in vivo. Functionally, the data demonstrated that PHD2 knockdown leads to increased glycolysis, while PHD2 overexpression resulted in suppressed glycolysis in colorectal cancer cells. In addition, the glycolytic activity was enhanced without PHD2 and normalized after PHD2 reconstitution. PHD2 was shown to inhibit colorectal tumor growth, suppress cancer cell proliferation and improve tumorbearing mice survival in vivo. Mechanically, it was found that PHD2 inhibits the expression of critical glycolytic enzymes (glucose transporter 1, hexokinase 2 and phosphoinositidedependent protein kinase 1). In addition, PHD2 inhibited Ikkßmediated NFκB activation in a hypoxiainducible factor1αindependent manner. In conclusion, the data demonstrated that PHD2/Ikkß/NFκB signaling has critical roles in regulating glycolysis and suggests that PHD2 potentially suppresses colorectal cancer.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
/
Neoplasias do Colo
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article