Evidence for non‐functional Dickkopf‐1 (DKK‐1) signaling in chronic lymphocytic leukemia (CLL)

Filipovich, Alexandra H.; Gandhirajan, Rajesh Kumar; Gehrke, Iris; Poll-Wolbeck, Simon Jonas; Kreuzer, Karl‐Anton

doi:10.1111/j.1600-0609.2010.01494.x

Cited by 14 publications

(10 citation statements)

References 17 publications

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“…Therefore, two pairs of primers were selected to examine the mRNA expression of LRP6: one for the extracellular domain of LRP6, responsible for DKK1 binding, and another for the intracellular region, essential for inhibiting GSK3β [22]. Of great note, neither the extracellular domain nor the intracellular domain of LRP6 were changed, although the expression of β-catenin was dramatically altered upon DKK1 up-regulation (Figure 6A) or knockdown (Figure 6B).…”

Section: Resultsmentioning

confidence: 99%

DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway

et al. 2013

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BackgroundRecently several reports have indicated that elevated expression of DKK1 is tightly associated with the progression of hepatocellular carcinoma (HCC). However, the biological function of DKK1 in HCC has not yet been well documented.MethodsIn this study, the role of DKK1 in tumor cell proliferation, migration and invasion was investigated using MTT, colony formation, wound scratch, transwell assays, and also human HCC samples.ResultsBoth gain- and loss-of-function studies showed that DKK1 did not influence the tumor cell proliferation and colony formation, while dramatically promoted HCC cell migration and invasion. Subsequent investigations revealed that β-catenin was an important target of DKK1. The blocking of β-catenin by pharmacological inhibitor antagonized the function of DKK1, whereas introduction of β-catenin by transfection with plasmids or treatment with GSK3β inhibitor phenocopied the pro-migration and pro-invasion effects of DKK1. We further disclosed that DKK1 exerted its pro-invasion function, at least in part, by promoting β-catenin expression, in turn, upregulating the expression of matrix metalloproteinase 7 (MMP7), which was independent of the canonical Wnt signaling pathway. Moreover, introduction of MMP7 significantly enhanced the ability of HCC cells to invade extracellular matrix gel in vitro. Consistently, in human HCC tissues, DKK1 level was positively correlated with β-catenin expression, as well as tumor metastasis.ConclusionTaken together, these results demonstrated that DKK1 is overexpressed in HCC; moreover, ectopic expression DKK1 promotes HCC cell migration and invasion at least partly through β-catenin/MMP7 signaling axis, suggesting that DKK1 may be a promising target for HCC therapy.

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Section: Resultsmentioning

confidence: 99%

DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway

et al. 2013

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“…LRP6 expression has been detected in primary CLL cells, albeit at low levels (22,23). As salinomycin could block Wnt-induced LRP6 phosphorylation and cause the degradation of LRP6 protein in HEK293 cells (Fig.…”

Section: Effects Of Salinomycin On Different Components Of Wnt Signalingmentioning

confidence: 87%

Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells

Choi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

350

275

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Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/ β-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.canonical Wnt antagonist | LRP6 stability | B-cell neoplasm

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“…It has been demonstrated that the Wnt signaling pathway is activated in CLL cells and that uncontrolled Wnt/ β -catenin signaling may contribute to the defect in apoptosis that characterizes this malignancy [30]. It is thought to be responsible for the extended survival of CLL cells in vivo [31]. In primary CLL cells, Wnt proteins are overexpressed, and physiological inhibitors of this pathway are inactivated [32].…”

Section: Wnt Signaling In Cancer and Chronic Leukemiamentioning

confidence: 99%

“…Normal B cells proved to have significantly higher levels of extracellular, DKK1-binding domain of LRP6. On the other hand, a truncated LRP6 without extracellular DKK1-binding domain could lead to an uncontrollable activation of Wnt signaling in CLL [31]. …”

Section: Wnt Signaling In Cancer and Chronic Leukemiamentioning

confidence: 99%

Understanding and Targeting the Wnt/β-Catenin Signaling Pathway in Chronic Leukemia

Thanendrarajan

Kim

Schmidt‐Wolf

2011

Leukemia Research and Treatment

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It has been revealed that the Wnt/β-catenin signaling pathway plays an important role in the development of solid tumors and hematological malignancies, particularly in B-cell neoplasia and leukemia. In the last decade there have been made experimental approaches targeting the Wnt pathway in chronic leukemia. In this paper we provide an overview about the current state of knowledge regarding the Wnt/β-catenin signaling pathway in chronic leukemia with special focus on therapeutic options and strategies.

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Evidence for non‐functional Dickkopf‐1 (DKK‐1) signaling in chronic lymphocytic leukemia (CLL)

Cited by 14 publications

References 17 publications

DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway

DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway

Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells

Understanding and Targeting the Wnt/β-Catenin Signaling Pathway in Chronic Leukemia

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