Targeting TRIM40 signaling reduces esophagus cancer development: A mechanism involving in protection of oroxylin A.
Int Immunopharmacol
; 137: 112362, 2024 Aug 20.
Article
in En
| MEDLINE
| ID: mdl-38901248
ABSTRACT
Oroxylin A (OA), a naturally active O-methylated flavone derived from Scutellaria baicalensis, is regarded as a potential drug with strong anticancer effects. Unfortunately, our understanding of the antineoplastic mechanism of oral exposure to such flavonoids is inadequate. Growing evidence has confirmed the important role of OA in the regulation of oxidative stress- and inflammatory-response-induced tissue injury. However, it remains unknown whether OA is capable of mitigating esophagus cancer (EC) progression and its potential molecular mechanism. Furthermore, the tripartite motif containing 40 (TRIM40) is a ubiquitin ligase that mediates the immune response. The potential molecular function of TRIM40 in regulating EC is largely unknown. We confirmed that OA-triggered oxidative stress markedly upregulates TRIM40. During the OA challenge, increased TRIM40 reduced oxidative stress and promoted the ER stress response. Inversely, deletion of TRIM40 facilitated oxidative stress and blocked cancer cell growth in vivo and in vitro. Mechanistically, in response to OA treatment, TRIM40 directly interacts with Keap1 and promotes ubiquitin-proteasome degradation, thus leading to the promotion of Nrf2 nuclear translocation and its downstream cascade activation, which increases antioxidant defense and cell survival. TRIM40 expression was positively correlated with Nrf2 expression and negatively associated with Keap1 expression in EC xenografts and human specimens. In addition, high TRIM40 expression correlates with poor patient survival in EC. The findings suggested that oral exposure to OA significantly mitigates EC development by targeting TRIM40 activity. These findings further elucidated the potential role of TRIM40 in EC progression by mediating Keap1 degradation, which could be considered a therapeutic target for the treatment of such a disease.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Flavonoids
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Esophageal Neoplasms
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Signal Transduction
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Oxidative Stress
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Ubiquitin-Protein Ligases
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NF-E2-Related Factor 2
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Tripartite Motif Proteins
Limits:
Animals
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Humans
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Male
Language:
En
Journal:
Int Immunopharmacol
Journal subject:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Year:
2024
Type:
Article
Affiliation country:
China