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Wnt/Ca2+ signaling: Dichotomous roles in regulating tumor progress (Review)

  • Authors:
    • Licong Jing
    • Hui Wang
    • Sheng Xia
    • Qixiang Shao
  • View Affiliations / Copyright

    Affiliations: Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
    Copyright: © Jing et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 399
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    Published online on: June 18, 2025
       https://doi.org/10.3892/ol.2025.15145
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Abstract

The Wnt signaling pathway is broadly categorized into two major classes: Canonical and non‑canonical pathways. The canonical Wnt pathway, which is also referred to as the Wnt/β‑catenin pathway, involves the nuclear translocation of β‑catenin. By contrast, non‑canonical Wnt pathways, including the Wnt/Ca2+ pathway and the Wnt/planar cell polarity pathway, function independently of β‑catenin nuclear translocation. Among these non‑canonical pathways, the Wnt/Ca2+ pathway influences cellular behavior by elevating intracellular Ca2+ concentrations. This pathway primarily regulates cytoskeletal remodeling, cell migration, polarity and immune responses, and serves a crucial role in cell proliferation, differentiation, embryonic development and tumorigenesis. Notably, Wnt/Ca2+ signaling exhibits dual functions in different tumor types, promoting tumorigenesis in certain cancers, whilst inhibiting it in others. The present review systematically summarizes research regarding the Wnt/Ca2+ signaling pathway, elucidates its mechanisms in cancer progression, and outlines current strategies for targeting the Wnt/Ca2+ signaling pathway in cancer, along with the associated challenges.
View Figures

Figure 1

Schematic diagram of the
Wnt/Ca2+ signaling pathway, created in BioRender. Jing,
L. (2025) https://BioRender.com/t20q988. The
Wnt/Ca2+ pathway is primarily activated by Wnt5a and
Wnt11 ligands, which bind to the FZD receptor on the cell membrane.
This interaction triggers the activation of G proteins and the FZD
adapter protein Dvl, which mediates the activation of PLC. PLC then
cleaves PIP2 into IP3 and DAG. Subsequently, IP3 binds to InsP3R on
the ER membrane, causing the release of Ca2+ from the
ER. In response to the decreased Ca2+ levels in the ER,
STIM1 proteins on the ER membrane activate the Orai protein in the
PM. The Orai protein tetramerizes to form the CRAC channel, which
mediates the influx of extracellular Ca2+ into the
cytoplasm. The increased cytoplasmic Ca2+ primarily
regulates three distinct pathways: i) With DAG, it activates PKC,
further stimulating CDC42, inducing actin polymerization and
promoting cell polarization and migration. This pathway also
cascades through the Wnt/PCP pathway; ii) it activates CaMKII,
stimulating TAK1, which then activates NLK to phosphorylate TCF,
inhibiting the β-catenin/TCF complex and blocking gene
transcription; and iii) it activates CaN, phosphorylating NFAT and
promoting downstream gene transcription. FZD, frizzled; G protein,
heterotrimeric guanine nucleotide-binding protein; Dvl, disheveled;
PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate;
IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; InsP3R,
inositol 1,4,5-trisphosphate receptors; ER, endoplasmic reticulum;
STIM1, stromal interaction molecule 1; PM, plasma membrane; CRAC,
calcium release-activated calcium; CDC42, cell division cycle 42;
Wnt/PCP, Wnt/planar cell polarity; CaMKII, calmodulin-dependent
protein kinase II; TAK1, transforming growth factor-β-activated
kinase 1; NLK, Nemo-like kinase;NFAT, nuclear factor of activated T
cells; TCF, T Cell Factor; CaN, calcineurin; NFAT, nuclear factor
of activated T cells.
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Copy and paste a formatted citation
Spandidos Publications style
Jing L, Wang H, Xia S and Shao Q: Wnt/Ca<sup>2+</sup> signaling: Dichotomous roles in regulating tumor progress (Review). Oncol Lett 30: 399, 2025.
APA
Jing, L., Wang, H., Xia, S., & Shao, Q. (2025). Wnt/Ca<sup>2+</sup> signaling: Dichotomous roles in regulating tumor progress (Review). Oncology Letters, 30, 399. https://doi.org/10.3892/ol.2025.15145
MLA
Jing, L., Wang, H., Xia, S., Shao, Q."Wnt/Ca<sup>2+</sup> signaling: Dichotomous roles in regulating tumor progress (Review)". Oncology Letters 30.2 (2025): 399.
Chicago
Jing, L., Wang, H., Xia, S., Shao, Q."Wnt/Ca<sup>2+</sup> signaling: Dichotomous roles in regulating tumor progress (Review)". Oncology Letters 30, no. 2 (2025): 399. https://doi.org/10.3892/ol.2025.15145
Copy and paste a formatted citation
x
Spandidos Publications style
Jing L, Wang H, Xia S and Shao Q: Wnt/Ca<sup>2+</sup> signaling: Dichotomous roles in regulating tumor progress (Review). Oncol Lett 30: 399, 2025.
APA
Jing, L., Wang, H., Xia, S., & Shao, Q. (2025). Wnt/Ca<sup>2+</sup> signaling: Dichotomous roles in regulating tumor progress (Review). Oncology Letters, 30, 399. https://doi.org/10.3892/ol.2025.15145
MLA
Jing, L., Wang, H., Xia, S., Shao, Q."Wnt/Ca<sup>2+</sup> signaling: Dichotomous roles in regulating tumor progress (Review)". Oncology Letters 30.2 (2025): 399.
Chicago
Jing, L., Wang, H., Xia, S., Shao, Q."Wnt/Ca<sup>2+</sup> signaling: Dichotomous roles in regulating tumor progress (Review)". Oncology Letters 30, no. 2 (2025): 399. https://doi.org/10.3892/ol.2025.15145
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