Regulation of Wnt Signaling Pathways at the Plasma Membrane and Their Misregulation in Cancer

Abstract

Wnt signaling is one of the key signaling pathways that govern numerous physiological activities such as growth, differentiation and migration during development and homeostasis. As pathway misregulation has been extensively linked to pathological processes including malignant tumors, a thorough understanding of pathway regulation is essential for development of effective therapeutic approaches. A prominent feature of cancer cells is that they significantly differ from healthy cells with respect to their plasma membrane composition and lipid organization. Here, we review the key role of membrane composition and lipid order in activation of Wnt signaling pathway by tightly regulating formation and interactions of the Wnt-receptor complex. We also discuss in detail how plasma membrane components, in particular the ligands, (co)receptors and extracellular or membrane-bound modulators, of Wnt pathways are affected in lung, colorectal, liver and breast cancers that have been associated with abnormal activation of Wnt signaling. Wnt-receptor complex components and their modulators are frequently misexpressed in these cancers and this appears to correlate with metastasis and cancer progression. Thus, composition and organization of the plasma membrane can be exploited to develop new anticancer drugs that are targeted in a highly specific manner to the Wnt-receptor complex, rendering a more effective therapeutic outcome possible.

Molecular Mechanisms of Antiproliferative Effects of Natural Chalcones

“…It regulates a broad spectrum of biological processes including cell differentiation and proliferation, embryo development, or apoptosis. Furthermore, abnormal activation of the Wnt/β-Catenin pathway has been shown in different cancers including colorectal, lung, liver, or breast cancer [ 209 ]. Additionally, experiments have also demonstrated that suppression of the Wnt pathway inhibits the proliferation of cancer cells.…”

WNT5B in Physiology and Disease

“…There are 10 members of the Frizzled (FZD) protein family, which serve as receptors for both the canonical and non-canonical signaling pathways. The pairing between specific FZDs and another receptor, such as low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6), receptor Tyr kinase-like orphan receptor 1 or 2 (ROR1/2) and receptor Tyr kinase (RYK), directs the downstream signaling pathway ( Azbazdar et al, 2021 ). Canonical WNT signaling is initiated by binding of WNT ligands (e.g., WNT3A and WNT10B) to a heterodimeric receptor complex formed by a Frizzled (FZD) and LRP5/6.…”

Key radioresistance regulation models and marker genes identified by integrated transcriptome analysis in nasopharyngeal carcinoma

“…As reported, the Wnt signaling pathway is one of the important pathways that regulate the proliferation, differentiation, and migration of cells, 20 and dysregulation of the Wnt signaling pathway is closely associated with the development of a variety of tumors such as lung cancer, liver cancer, and breast cancer. 21 Moreover, three immune‐related pathways, including T‐cell receptor signaling pathway were also enriched, suggesting that the immune status of T cells might be associated with radiation resistance.…”