Oxidative Distress Induces Wnt/β-Catenin Pathway Modulation in Colorectal Cancer Cells: Perspectives on APC Retained Functions.

Teresa Catalano,Maria Cristina Curia,Alessio Ferrone,Federico Selvaggi,Giuseppina Bologna,Paola Lanuti,Maria Carmela Di Marcantonio,Carmelo Moscatello,Gitana Maria Aceto,Roberto Cotellese,Emira D’Amico,Rossano Lattanzio

doi:10.3390/cancers13236045

Teresa Catalano, Maria Cristina Curia + Show 10 more

Open Access

https://doi.org/10.3390/cancers13236045

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Abstract

Colorectal cancer (CRC) is a multistep process that arises in the colic tissue microenvironment. Oxidative stress plays a role in mediating CRC cell survival and progression, as well as promoting resistance to therapies. CRC progression is associated with Wnt/β-Catenin signaling dysregulation and loss of proper APC functions. Cancer recurrence/relapse has been attributed to altered ROS levels, produced in a cancerous microenvironment. The effect of oxidative distress on Wnt/β-Catenin signaling in the light of APC functions is unclear. This study evaluated the effect of H2O2-induced short-term oxidative stress in HCT116, SW480 and SW620 cells with different phenotypes of APC and β-Catenin. The modulation and relationship of APC with characteristic molecules of Wnt/β-Catenin were assessed in gene and protein expression. Results indicated that CRC cells, even when deprived of growth factors, under acute oxidative distress conditions by H2O2 promote β-Catenin expression and modulate cytoplasmic APC protein. Furthermore, H2O2 induces differential gene expression depending on the cellular phenotype and leading to favor both Wnt/Catenin-dependent and -independent signaling. The exact mechanism by which oxidative distress can affect Wnt signaling functions will require further investigation to reveal new scenarios for the development of therapeutic approaches for CRC, in the light of the conserved functions of APC.

Highlights

Colorectal cancer (CRC) is the third most prevalent cancer worldwide, since 1.9 million new cases and approximately 935,000 deaths occurred in 2020 according to the World Health Organization [1]
We analyzed the effects induced by the exposure to H2O2 on viability and proliferation of HCT116, SW480 and SW620 cell lines
The HCT116 cells were characterized by adenomatous polyposis coli (APC) wild type, mutated β-Catenin (CTNNB-1), LRP6 and ROR2 [41] as well as microsatellite instability (MSI) that was caused by biallelic mutation in MLH-1 gene [42]

Summary

Introduction

Colorectal cancer (CRC) is the third most prevalent cancer worldwide, since 1.9 million new cases and approximately 935,000 deaths occurred in 2020 according to the World Health Organization [1]. CRC usually takes years to develop and complex interactions between genetic and environmental factors occur during this process [3,4]. Colorectal carcinogenesis goes through a multistep process, arising in the majority of cases from an adenoma that has the potential to evolve into carcinoma by the accumulation of additional somatic mutations and epigenetic alterations through interactions with the tissue microenvironment [5]. These events are primarily associated with Wingless/It (Wnt)/β-Catenin signaling dysregulation [6,7]. Wnt signals are transduced into cells through the canonical (β-catenin dependent) and non-canonical (β-catenin independent) pathways [8,9,10]

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