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

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.

PHGDH Inhibitor CBR-5884 Inhibits Epithelial Ovarian Cancer Progression via ROS/Wnt/β-Catenin Pathway and Plays a Synergistic Role with PARP Inhibitor Olaparib

“…Meanwhile, we tested the EMT-related genes, such as E-cadherin, N-cadherin, vimentin, and Snail. The results showed that CBR-5884 exerts an antitumor effect through activating ROS/Wnt/ β -catenin pathway, which is consistent with the reported results in other malignant tumors [ 24 , 27 – 31 ]. At last, we verified the effect of CBR-5884 in vivo through nude mice xenograft.…”

“…Reactive oxygen species which are produced by cell metabolic activities attach importance to cell signal transduction and homeostasis and regulate cell proliferation, apoptosis, and differentiation [24][25][26]. Recent studies suggested that oxidative stress induced by ROS can regulate Wnt/β-catenin signaling pathway in colorectal, breast, lung, pancreatic, and liver cancer [24,[27][28][29][30][31]. Therefore, studying the effect of CBR-5884 and NAC in the regulation of Wnt/β-catenin pathway is significant.…”

Systematic analysis of cancer‐specific synthetic lethal interactions provides insight into personalized anticancer therapy

“…Further experimental validation verified the synthetic lethal interaction of APC and GFER in a colon cancer cell line (Figs 5 and 6). APC , mostly known as a tumour suppressor involved in WNT signalling, is recurrently altered in colorectal cancer [45,46]. APC deficiency can activate a TCF4‐TDO2‐AhR‐CXCL5 circuit that impacts multiple cancer hallmarks via autonomous and non‐autonomous mechanisms, illuminating a genotype‐specific vulnerability in colorectal cancers [47].…”

Effects of H2O2 Treatment Combined With PI3K Inhibitor and MEK Inhibitor in AGS Cells: Oxidative Stress Outcomes in a Model of Gastric Cancer

“…Physiologically, reactive radical-type oxygen species lead to the final formation of hydrogen peroxide (H 2 O 2 ), a highly diffusible molecule ( 39 ). This molecule produced by healthy cells is involved in multiple intracellular stress response signals ( 40 ). However, when H 2 O 2 is over-produced or inadequately detoxified, it can induce excessive intracellular production of 7,8-dihydro-8-oxoguanine (8-oxoG) ( 41 ).…”