Wnt3a suppresses Wnt/β-catenin signaling and cancer cell proliferation following serum deprivation

• Wnt3a has a novel inhibitory role on Wnt/β-catenin signaling in cancer cells.
• Persistent excessive Wnt3a stimulation suppressed β-catenin and cell proliferation.
• Inhibitory effects of Wnt3a were mediated by LRP6 endocytosis.
• Inhibitory effects of Wnt3a were abolished by Nystatin or FilipinIII.
• Serum deprivation suppressed cell proliferation via elevating Wnt3a expression.

Canonical Wnt/β-catenin signaling is often aberrantly activated in tumor cells and required for tumor growth. The internalization of Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) induced by Wnt ligands is commonly thought to be critical for Wnt/β-catenin signaling activation. However, in contrast to theses previous studies, we here show that persistent excessive stimulation with a canonical Wnt ligand Wnt3a could induce a long-term decreased expression level of membrane LRP6, which prevented nuclear β-catenin accumulation and tumor cell;proliferation. Importantly, Wnt3a was robustly upregulated following serum deprivation. The upregulated Wnt3a under serum deprivation was responsible for LRP6 internalization, decreased accumulation of nuclear β-catenin, and further inhibition of tumor cell proliferation. It has well been known that insufficient blood supply during tumor development occurs frequently, causing a worsening environment for tumor growth. Therefore, these results reveal a novel inhibitory role of Wnt3a on canonical Wnt/β-catenin signaling and cancer cell proliferation when there is an insufficient blood supply during tumor development, which might be a potential mechanism for tumor evasion within a worsening environment.