Nuclear Accumulation of β-Catenin in Cancer Stem Cell Radioresistance and Stemness in Human Colon Cancer

Abstract

Background/Aim: The aim of this study was to examine whether the Wnt/β-catenin signal activation is a cause of radioresistance in colon cancer by assessing the β-catenin localization and its correlation with cancer stem cells (CSCs). Materials and Methods: The nuclear levels of β-catenin, the hallmark of Wnt activation, were analyzed in HCT116 and SW480 cells by immunohistochemistry, before and after irradiation. Further, we assessed CSC populations by staining for aldehyde dehydrogenase-1 (ALDH1) and CD44. Results: β-catenin was localized predominantly in the nucleus and plasma membrane in SW480 and HCT116 cells, respectively. Compared to HCT116 cells, SW480 cells displayed higher Wnt activation. At 24 h after irradiation, most of the DSBs in SW480 cells were repaired, but were still present in HCT116 cells. Additionally, compared to HCT116 cells, a significantly higher proportion of SW480 cells were ALDH1-and CD44-positive. Conclusion: Colon cancers with nuclear β-catenin accumulation demonstrated greater radio-resistance with a higher number of CSCs.There are two Wnt/β-catenin signaling pathways: the canonical pathway and the non-canonical pathway (1, 2). β-catenin is the key molecule in the canonical Wnt pathway. In Wnt-off state, βcatenin in the cytoplasm is within a protein complex composed of adenomatous polyposis coli (APC), Axin, glycogen synthase kinase 3β (GSK3β), and casein kinase 1α (CK1α), and phosphorylated by GSK3β and CK1α. Then, β-catenin is ubiquitinated and targeted for destruction by the proteasome. As a result, the amount of β-catenin is low. Conversely, in the Wnton state, Wnt ligands bind to the receptor complex composed of a Frizzled (Fz) receptor and low-density lipoprotein receptorrelated proteins (LRP5/6). This receptor recruits Disheveled (Dvl) to the plasma membrane. Dvl forms a complex with Axin, Fz, and LRP5/6 and acts as a direct competitive inhibitor of GSK3β. Thus, β-catenin escapes phosphorylation and accumulates in the cytoplasm. The stabilized β-catenin translocates into the nucleus, where it serves as a transcriptional co-activator and influences gene transcription. Thus, β-catenin localization to the nucleus reflects Wnt activity (3-5).The canonical Wnt/β-catenin signaling pathway plays an important role in cell proliferation, growth, and differentiation (6, 7). Mutations in Wnt signaling pathway components cause many diseases, including cancer. Furthermore, dysregulation of the Wnt signaling pathway is associated with the expansion of stem cell and progenitor cell lineages and is also highly associated with carcinogenesis (8-10). Most colorectal cancer (CRC) cases are caused by mutations in Wnt signaling pathway components (11-13). Originally, a mutation in the APC gene was associated with familial adenomatous polyposis (FAP). Approximately 1% of FAP cases progress to CRC (14,15). Furthermore, 85% of sporadic intestinal neoplasia cases have mutations in APC, whereas activating 6575

Altered Wnt5a expression affects radiosensitivity of non‑small cell lung cancer via the Wnt/β‑catenin pathway

“…Increasing evidence suggest that the Wnt/β-catenin pathway is associated with radioresistance of cancer cells (7,30). The enhanced nuclear translocation of β-catenin was more evident in radioresistance cells (31)(32)(33). Consistent with these findings, the present study demonstrated that Wnt5a knockdown decreased nuclear β-catenin expression, whereas overexpression of Wnt5a enhanced nuclear β-catenin expression.…”

ALDH1: A potential therapeutic target for cancer stem cells in solid tumors

“…ALDH1 plays a vital role in CRC and promotes the metastasis and proliferation of CRC stem cells through various classical pathways. Studies have suggested that the high expression of ALDH1 in CRC is related to the Wnt/β-catenin pathway ( 82 , 89 , 90 ), hsa_circ_0001806/miR-193a-5p/, COL1A1 axis ( 89 ), PI3K/AKT/mTOR signaling pathway ( 91 ), CXCL2/CXCR2 axis ( 92 ), miR-200-ZEB1/SANI2 axis ( 88 ). Additionally, ALDH1B1 may maintain the CSC phenotype and promote cancer cell growth by protecting cells from DNA damage ( 87 ).…”

Exosomes in the Tumor Microenvironment: From Biology to Clinical Applications

“…The loss of E-cadherin, mediated by these non-coding RNAs [188], promotes β-catenin release into the cytoplasm [189]. Once translocated to the nucleus, β-catenin downregulates not only cell-junction-related genes (E-cadherin and claudin-7) [89,190] but also upregulates stemness-related genes, facilitating the formation of CSCs [191][192][193].…”