Pivotal role of AKR1B1 in pathogenesis of colitis associated colorectal carcinogenesis.
Int Immunopharmacol
; 119: 110145, 2023 Jun.
Article
en En
| MEDLINE
| ID: mdl-37044030
Identifying the target linking inflammation and oxidative stress to aggravate the disease progression will help to prevent colitis associated carcinogenesis. Since AKR1B1 overexpression is observed in inflammatory diseases and various cancers, we have investigated the role of AKR1B1 in colitis-associated colon carcinogenesis with the aid of epalrestat and its potent analogue NARI-29 (investigational molecule) as pharmacological probes. A TNF-α inducible NF-κB reporter cell line (GloResponse™ NF-κB-RE-luc2P HEK293) and dextran sodium sulfate (DSS) and 1,2 dimethyl hydrazine (DMH))-induced mouse model was used to investigate our hypothesis in vitro and in vivo. Clinically, an increased expression of AKR1B1 was observed in patients with ulcerative colitis. Our in vitro and in vivo findings suggest that the AKR1B1 modulated inflammation and ROS generation for the progression of colitis to colon cancer. AKR1B1 overexpression was observed in DSS + DMH-treated mice colons. Moreover, we could observe histopathological changes like immune cell infiltration, aberrant crypt foci, and tumour formation in DC groups. Mechanistically, we have witnessed modulation of the IKK/IκB/NF-κB and Akt/FOXO-3a/DR axis, increased inflammatory cytokines, increased expression of proliferative markers, Ki-67 and PCNA, and accumulation of ß-catenin in the colon epithelium. However, pharmacological inhibition of AKR1B1 using NARI-29 or EPS has reversed the clinical, histopathological, and molecular alterations induced by DSS + DMH, confirming the obvious role of AKR1B1 in the promotion of colitis-associated carcinogenesis. In conclusion, our findings suggest that AKR1B1 targeted therapy could be a promising strategy for preventing CA-CRC and NARI-29 could be developed as a potent AKR1B1 inhibitor.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Colitis Ulcerosa
/
Colitis
/
Neoplasias del Colon
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Int Immunopharmacol
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Año:
2023
Tipo del documento:
Article
País de afiliación:
India
Pais de publicación:
Países Bajos