Dickkopf-1: Current knowledge and related diseases

Huang, Yu; Liu, Lie; Liu, Aiguo

doi:10.1016/j.lfs.2018.08.019

Cited by 74 publications

(59 citation statements)

References 52 publications

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“…During early embryogenesis, DKK1 is released from the endoderm in order to control cell death and differentiation [ 358 ]. As a result, over-expression of DKK1 leads to synaptic loss and neuronal apoptosis, making it a common marker for neuronal death in neurodegenerative diseases [ 359 ]. In the aging brain, Wnt signaling was identified to generally diminish [ 360 ], while DKK1 remained up-regulated [ 361 ].…”

Section: Molecular Bases Of Brain-bone Crosstalkmentioning

confidence: 99%

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Otto

Knapstein

Jahn

et al. 2020

IJMS

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As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain ‘efferent’, signaling from brain to bone, this review emphasizes the emergence of bone as a crucial ‘afferent’ regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.

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Section: Molecular Bases Of Brain-bone Crosstalkmentioning

confidence: 99%

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Otto

Knapstein

Jahn

et al. 2020

IJMS

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“…The reduction of β-catenin nuclear localization found a functional effect in the modification of the expression of some target genes involved in the activity and in the regulation of this pathway. We provided indications that trabectedin leads to the increased expression of CTNNBIP1 (β-catenin-interacting-protein-1) and DKK1 (Dickkopf-related protein) that inhibit [27] and antagonize [28,29] the Wnt signaling pathway, respectively. The apparent discrepancy of the DKK1 mRNA increase found its rationale in the evidence that alkylating drugs directly stimulate DKK1 gene expression [30].…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells

Abate

Rossini

Bonini

et al. 2020

Cancers

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Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regimen to be added to mitotane is a chemotherapy including etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Evidence indicates that ACC seems to be sensitive to alkylating agents. Trabectedin is an anti-tumor drug that acts as an alkylating agent with a complex mechanism of action. Here, we investigated whether trabectedin could exert a cytotoxic activity in in vitro cell models of ACC. Cell viability was evaluated by MTT assay on ACC cell lines and primary cell cultures. The gene expression was evaluated by q-RT-PCR, while protein expression and localization were studied by Western blot and immunocytochemistry. Combination experiments were performed to evaluate their interaction on ACC cell line viability. Trabectedin demonstrated high cytotoxicity at sub-nanomolar concentrations in ACC cell lines and patient-derived primary cell cultures. The drug was able to reduce /β catenin nuclear localization, although it is unclear whether this effect is involved in the observed cytotoxicity. Trabectedin/mitotane combination exerted a synergic cytotoxic effect in NCI-H295R cells. Trabectedin has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of trabectedin with mitotane provides the rationale for testing this combination in a clinical study.

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“…As it has been reported that Dkk1 is an inhibitor of the canonical Wnt/β-catenin signaling pathway (Huang et al, 2018), we determined the β-catenin level after Dox treatment and found that the protein expression of β-catenin was downregulated in Doxtreated H 9 C 2 cells and heart tissues ( Fig. 6A,B).…”

Section: Involvement Of Dkk1 In Dox-induced Cardiotoxicity In H 9 C 2mentioning

confidence: 90%

“…Dkk1, the founding member of Dkk family, is best studied and functions as an antagonist of canonical Wnt/β-catenin signaling pathway. Dkk1 is involved in many physiological and pathological processes, and exerts an important role in the development of many diseases (Huang et al, 2018). It has been reported that Dkk1 promoted ischemia-induced DNA damage by downregulating basal LRP5 and LRP6 (LRP5/6) levels and then altering G-protein-coupled receptor (GPCR) signals (Wo et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway

Liu

et al. 2019

Journal of Cell Science

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The cancer clinical therapy of doxorubicin (Dox) treatment is limited by its life-threatening cardiotoxic effects. Dickkopf-1 (Dkk1), the founding and best-studied member of the Dkk family, functions as an antagonist of canonical Wnt/β-catenin. Dkk1 is considered to play a broad role in a variety of biological processes, but its effects on Dox-induced cardiomyopathy are poorly understood. Here, we found that the level of Dkk1 was significantly increased in Dox-treated groups, and this increase exacerbated Dox-induced cardiomyocyte apoptosis and mitochondrial dysfunction. Overexpressing Dkk1 aggravated Dox-induced cardiotoxicity in H 9 C 2 cells. Similar results were detected when adding active Dkk1 protein extracellularly. Conversely, adding specific antibody blocking extracellular Dkk1 attenuated the cardiotoxic response to Dox. Adenovirus encoding Dkk1 was transduced through intramyocardial injection and exacerbated Dox-induced cardiomyocyte apoptosis, mitochondrial damage and heart injury in vivo. Furthermore, Wnt/βcatenin signaling was inhibited during Dox-induced cardiotoxicity, and the re-activation of β-catenin prevented the effect of overexpressed Dkk1 and Dox-induced cardiotoxicity. In conclusion, these results reveal the crucial role of the Dkk1-Wnt/β-catenin signaling axis in the process of Dox-induced cardiotoxicity and provide novel insights into the potential mechanism of cardiomyopathy caused by clinical application of Dox.

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Dickkopf-1: Current knowledge and related diseases

Cited by 74 publications

References 52 publications

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells

Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway

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