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Differential Regulation of Wingless-Wnt/c-Jun N-Terminal Kinase Crosstalk via Oxidative Eustress in Primary and Metastatic Colorectal Cancer Cells

Authors :
Gitana Maria Aceto
Sara Pagotto
Francesco Domenico Del Pizzo
Concetta Saoca
Federico Selvaggi
Rosa Visone
Roberto Cotellese
M’hammed Aguennouz
Rossano Lattanzio
Teresa Catalano
Source :
Biomedicines, Vol 12, Iss 8, p 1816 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

Abstract

In the tumor microenvironment (TME), ROS production affects survival, progression, and therapy resistance in colorectal cancer (CRC). H2O2-mediated oxidative stress can modulate Wnt/β-catenin signaling and metabolic reprogramming of the TME. Currently, it is unclear how mild/moderate oxidative stress (eustress) modulates Wnt/β-catenin/APC and JNK signaling relationships in primary and metastatic CRC cells. In this study, we determined the effects of the H2O2 concentration inducing eustress on isogenic SW480 and SW620 cells, also in combination with JNK inhibition. We assessed cell viability, mitochondrial respiration, glycolysis, and Wnt/β-catenin/APC/JNK gene and protein expression. Primary CRC cells were more sensitive to H2O2 eustress combined with JNK inhibition, showing a reduction in viability compared to metastatic cells. JNK inhibition under eustress reduced both glycolytic and respiratory capacity in SW620 cells, indicating a greater capacity to adapt to TME. In primary CRC cells, H2O2 alone significantly increased APC, LEF1, LRP6, cMYC and IL8 gene expression, whereas in metastatic CRC cells, this effect occurred after JNK inhibition. In metastatic but not in primary tumor cells, eustress and inhibition of JNK reduced APC, β-catenin, and pJNK protein. The results showed differential cross-regulation of Wnt/JNK in primary and metastatic tumor cells under environmental eustress conditions. Further studies would be useful to validate these findings and explore their therapeutic potential.

Details

Language :
English
ISSN :
22279059
Volume :
12
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Biomedicines
Publication Type :
Academic Journal
Accession number :
edsdoj.4243d0169bf34fb0939aa9a6ba6ca21b
Document Type :
article
Full Text :
https://doi.org/10.3390/biomedicines12081816