Secreted Wnt6 mediates diabetes-associated centrosome amplification via its receptor FZD4

Abstract

We recently published that type 2 diabetes promotes cell centrosome amplification via upregulation of Rho-associated protein kinase 1 (ROCK1) and 14-3-3 protein-σ (14-3-3σ). This study further investigates the molecular mechanisms underlying diabetes-associated centrosome amplification. We found that treatment of cells with high glucose, insulin, and palmitic acid levels increased the intracellular and extracellular protein levels of Wingless-type MMTV integration site family member 6 (Wnt6) as well as the cellular level of β-catenin. The treatment also activated β-catenin and promoted its nuclear translocation. Treatment of cells with siRNA species for Wnt6, Frizzled-4 (FZD4), or β-catenin as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture medium could all attenuate the treatment-triggered centrosome amplification. Moreover, we showed that secreted Wnt6-FZD4-β-catenin was the signaling pathway that was upstream of ROCK1 and 14-3-3σ. We found that advanced glycation end products (AGEs) were also able to increase the cellular and extracellular levels of Wnt6, the cellular protein level of β-catenin, and centrosome amplification. Treatment of the cells with siRNA species for Wnt6 or FZD4 as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture could all inhibit the AGEs-elicited centrosome amplification. In colon tissues from a diabetic mouse model, the protein levels of Wnt6 and 14-3-3σ were increased. In conclusion, our results showed that the pathophysiological factors in type 2 diabetes, including AGEs, were able to induce centrosome amplification. It is suggested that secreted Wnt6 binds to FZD4 to activate the canonical Wnt6 signaling pathway, which is upstream of ROCK1 and 14-3-3σ, and that this is the cell signaling pathway underlying diabetes-associated centrosome amplification.

Function expansion of antitumor transcriptional activator NFE2L1 by the original discovery of its non-transcription factor activity

“…The expression of WNT6 gene was decreased after overexpression of NFE2L1 or NFE2L1 ΔC . However, FZD4 and FZD8, genes encoding WNT6's receptors [36], were increased ( Fig. 5F).…”

The complex role of Wnt ligands in type 2 diabetes mellitus and related complications

“…The activation of ATF3/NFAT axis causes podocyte injury during the development of DN, and ATF3 is increased in glomeruli from proteinuric patients with DP, and Wnt6 is up‐regulated in ATF3‐overexpressed podocytes and identified as a target of this axis, indicating Wnt6 may aggravate podocyte injury and loss 104 . Furthermore, the activation of Wnt6/β‐catenin pathway in diabetic context establishes a pathological link between T2DM and cancer due to the inducing effect of this signalling on the amplification of centrosome, a symbolic event associated with high‐grade tumours and poor prognosis 105 . Thus, further studies are needed to explore the role of Wnt6 in the development of T2DM and related complications.…”

“… 104 Furthermore, the activation of Wnt6/β‐catenin pathway in diabetic context establishes a pathological link between T2DM and cancer due to the inducing effect of this signalling on the amplification of centrosome, a symbolic event associated with high‐grade tumours and poor prognosis. 105 Thus, further studies are needed to explore the role of Wnt6 in the development of T2DM and related complications.…”

Binding between ROCK1 and DCTN2 triggers diabetes‑associated centrosome amplification in colon cancer cells

“…In vitro experiments have identified that the pathophysiological factors in type 2 diabetes, including high glucose, insulin and free fatty acids (such as palmitic acid), are potent inducers, and that the centrosomal translocation of Rho-associated protein kinase 1 (ROCK1) is a signal for diabetes-associated centrosome amplification (6). Moreover, inhibition of ROCK1 partially attenuated centrosome amplification (6,20). These results suggest that centrosome amplification may be a candidate mechanism for the association between type 2 diabetes and cancer development, and that type 2 diabetes may present a natural model to investigate the roles of centrosome amplification in cancer.…”

“…In humans, the ROCK1 genotype was found to be associated with colon cancer in men (25), and is a candidate prognostic marker for vulvar cancer (26). Our previous studies revealed that ROCK1 signaling promotes diabetes-associated centrosome amplification (6,20). However, inhibiting ROCK1 only partially suppresses centrosome amplification, indicating that other factors are involved.…”