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

Abstract

It has been reported that upregulation of wingless-type protein 5a (Wnt5a) is associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). Wnt5a expression is often upregulated in radiation-resistant NSCLC cells. However, the biological functions or molecular mechanisms of radiosensitivity in NSCLC remain unknown. In the present study, MTT assay and flow cytometric analysis were performed to assess the effect of overexpression or knockdown of Wnt5a and/ or radiation on the proliferation and apoptosis of NSCLC cells. Furthermore, western blot analysis was performed to detect canonical Wnt signaling (β-catenin) in H1650 and A549 cells. The results demonstrated that Wnt5a knockdown combined with irradiation inhibited proliferation and induced apoptosis in NSCLC cells compared with Wnt5a knockdown or radiotherapy alone. In addition, the combination of Wnt5a knockdown and irradiation decreased nuclear and increased cytoplasmic β-catenin expression in H1650 and A549 cells, the effects of which were reversed following overexpression of Wnt5a. The combination of overexpressing Wnt5a and irradiation resulted in significant tumor regression, while β-catenin knockdown reversed Wnt5a overexpression-induced NSCLC cell proliferation. Taken together, these results suggest that Wnt5a may be involved in the activation of β-catenin-dependent canonical Wnt signaling, and thus may influence the effectiveness of radiation therapy in NSCLC.

Crosstalk between lncRNAs and Wnt/β-catenin signaling pathways in lung cancers: From cancer progression to therapeutic response

“…Also, it was revealed that Wnt5a expression could affect the response of NSCLC cell lines to radiotherapy. The combination of Wnt5a knockdown and irradiation leaded to decrease translocation of β-catenin from the cytoplasm to the nucleus, which had a connection to the neoplastic features of NSCLC, such as tumor proliferation and apoptosis [ 20 ]. β-catenin proteins played important roles in tumor formation, and inhibiting LC pathogenesis and delaying LC progression [ 21 ].…”

Wnt/β-catenin signaling in the development and therapeutic resistance of non-small cell lung cancer

“…WNT5A expression is often upregulated in radiation-resistant NSCLC cells (Table 4 ). Mechanistic investigation indicated that altered WNT5A expression affects radiosensitivity of NSCLC via Wnt/β-catenin pathway [ 228 ]. Disabled-2 (Dab2) is known as a tumor suppressor and Wnt pathway inhibitor.…”

Natural compounds: Wnt pathway inhibitors with therapeutic potential in lung cancer

“…Overexpression of MDR-associated transporters is the key mechanism by which the aberrant activation of Wnt/β-catenin signaling results in the induction of cancer MDR ( Ghandadi et al, 2019 ). The level of Wnt/β-catenin activity is positively correlated with resistance to several common chemotherapeutic drugs, such as paclitaxel and cisplatin, and radiation used in the treatment of LC ( Yang et al, 2016b ; Datta et al, 2019 ; Li et al, 2022 ). Frequently used adjuvant chemotherapy agents activate β-catenin-dependent signaling, which results in the upregulation of the expression and activity of multidrug-resistant protein 1 and other multidrug efflux transporters ( Vesel et al, 2017 ).…”

“…For example, the upregulation of β-catenin signaling may promote cisplatin resistance in LUAD cells through the overexpression of the BCL-XL gene ( Zhang J. et al, 2016 ). Experiments have revealed that blocking Wnt signaling increases the radiosensitivity of LC cells ( Wu et al, 2016 ; Li et al, 2022 ). Although this protective effect is attributed to downstream effectors of Wnt/β-catenin signaling, the more general mechanism of stress remains unclear ( Lee et al, 2013 ).…”