Wnt/β-catenin signaling pathway: an attractive potential therapeutic target in osteosarcoma

Abstract

Osteosarcoma (OS) is the most common bone malignancy in children and adolescents, and although current neoadjuvant chemotherapy has shown efficacy against OS, the long-term survival rate for patients with OS remains low, highlighting the need to find more effective treatments. In cancer cells, abnormal activation of signaling pathways can widely affect cell activity from growth and proliferation to apoptosis, invasion and metastasis. Wnt/β-catenin is a complex and unique signaling pathway that is considered to be one of the most important carcinogenic pathways in human cancer. Research have confirmed that the Wnt/β-catenin signaling pathway is an important driving factor for the occurrence and development of osteosarcoma, and abnormal activation of this pathway can promote the pathological processes of cell proliferation, invasion, migration, tumor angiogenesis and chemical resistance of osteosarcoma. However, inhibition of Wnt/β-catenin signaling pathway can effectively inhibit or reverse the above pathological processes. Therefore, manipulating the expression or function of the Wnt/β-catenin pathway may be a potential targeted pathway for the treatment of OS. In this review, we describe the characteristics of the Wnt/β-catenin signaling pathway and summarize the role and mechanism of this pathway in OS. This paper discusses the therapeutic significance of inhibiting or targeting Wnt/β-catenin pathway in OS and the shortcomings of current studies on this pathway in OS and the problems to be solved. This review helps us to understand the role of Wnt/β-catenin on OS, and provides a theoretical basis and new ideas for targeting Wnt/β-catenin pathway as a therapeutic target for OS.

Keywords: Wnt/β-catenin; chemotherapy; mechanism; osteosarcoma (OS); targeted therapy.

Figure 1

Classic Wnt/β-catenin pathway cascade diagram. The figure on the left shows the deactivation of the Wnt pathway. In the absence of Wnt signaling, β-catenin in the cytoplasm is recognized, folded, and phosphorylated by a destructive complex composed of scaffold proteins Axin, APC, GSK3β, and CK1, and targeted for degradation by a β-TRCP-mediated proteomic mechanism. The figure on the right shows activation of the Wnt pathway. The signal induces double phosphorylation of LRP6 by CK1 and GSK3-β via the Fizzled receptor and LRP5/6 co-receptor complex, which allows the axon-containing protein complex to transfer from the cytoplasm to the plasma membrane. Dsh is also recruited to the cell membrane and binds to Fizzied, and Axin binds to phosphorylated LRP5/6. The complex forms on the Fizzled/LRP5/6 membrane and induces stabilization of β-catenin by separating and/or degrading axons. β-catenin, which accumulates in the cytoplasm, translocates into the nucleus and, together with the transcription factor TCF, drives the expression of downstream target genes.

Figure 2

Illustration of a planar cell polarity transition cascade. Wnt signal transduction via Fizzled independent of LRP5/6 leads to Dsh activation. Dsh mediates the activation of Rho via Daam1, which activates Rho kinase (ROCK). Daam1 also mediates actin polymerization via the actin binding protein Profilin. Dsh also mediates the activation of Rac, which in turn activates JNK. Signals from Rock, JNK, and Profilin are integrated into cytoskeletal changes in cell polarization and movement during gastrum formation.

Figure 3

Schematic diagram of Wnt/Ca²⁺ signaling cascade. The Wnt signaling via Fizzled mediates the activation of Dsh through g protein activation. Dishevelled activates phosphodiesterase PDE, which inhibits PKG and in turn inhibits Ca²⁺ release. Dsh activates IP3 via PLC, resulting in the release of intracellular Ca²⁺, which activates CamK11 and calcineurin. NF-AT activation by calcineurin regulates the fate of ventral cells. CamK11 activates TAK and NLK, inhibits β-catenin/TCF function and negatively regulates dorsal axis formation. DAG mediates tissue separation and cell motility during gastrulation through PKC activation of CDC42.

Figure 4

The role of the Wnt/β-catenin pathway in the development of OS. Activation of this signaling pathway regulates OS by promoting tumor cell proliferation, epithelial-mesenchymal transformation and tumor cell invasion and metastasis, angiogenesis and chemical resistance, and inhibiting apoptosis.