Targeting the Wnt pathway in cancer: The emerging role of Dickkopf-3

Veeck, Jürgen; Dahl, Edgar

doi:10.1016/j.bbcan.2011.09.003

Cited by 147 publications

(182 citation statements)

References 108 publications

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“…While Dkk2 activates the Wnt/β-catenin signaling pathway (the canonical Wnt signaling pathway), Dkk1, 3 and 4 inactivate Wnt signaling. Dkk3 primarily binds with LRP5/6 and acts as an antagonist of the Wnt/β-catenin signaling pathway (the canonical Wnt signaling pathway) (4,10,18). It is also reported that Dkk3 inhibits other Wnt transduction pathways such as the Wnt/JNK signaling pathway in tumor cells (43).…”

Section: Discussionmentioning

confidence: 99%

“…Incubation with anti-DKK1 antibody induces apoptosis in A549 cells through the caspase-dependent pathway in vitro and suppresses the growth of A549 and H2170 lung cancer cells in nude mice (23). The tumor suppressor role of Dkk3 in NSCLC is twofold: DKK3 knockdown accelerates NSCLC cell proliferation, whereas Dkk3 overexpression hinders the growth of NSCLC cells through the induction of apoptosis and cell cycle disturbance (15)(16)(17)(18). It is thus conceivable that Dkk3, a Wnt inhibitor harboring tumor-suppressive activity, may exert similar functions such as its homologue Dkk1, which hinders NSCLC cell growth synergistically with cisplatin (18).…”

Section: Discussionmentioning

confidence: 99%

“…Although considered a tumor suppressor, the inactivation of Dkk3 alone is not sufficient for tumor initiation as the knockout of Dkk3 in mice did not increase tumor incidence (48). Moreover, instead of favoring tumor growth as assumed, Dkk3 knockdown favors apoptosis as in the case of Dkk3 overexpression in NSCLC cells (10,(15)(16)(17)(18)49). According to Jung et al, siRNA-mediated DKK3 knockdown enables H460 cells to detach from the bottom of the culture plate, as well as to initiate the apoptotic process as marked by an increase of cyclin-dependent kinases (CDK) D1 and E. DKK3 knockdown also increases the intracellular levels of reactive oxygen species (ROS) and the expression of P53, p21 and Bax (49).…”

Section: Discussionmentioning

confidence: 99%

“…The tumor suppressor role of Dkk3 in NSCLC is twofold: DKK3 knockdown accelerates NSCLC cell proliferation, whereas Dkk3 overexpression hinders the growth of NSCLC cells through the induction of apoptosis and cell cycle disturbance (15)(16)(17)(18). It is thus conceivable that Dkk3, a Wnt inhibitor harboring tumor-suppressive activity, may exert similar functions such as its homologue Dkk1, which hinders NSCLC cell growth synergistically with cisplatin (18). To the best of our knowledge however, the present study is the first one to show an association of Dkk3 and cisplatin resistance in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“…While DKK3 knockdown stimulates the proliferation of lung cancer cells, DKK3 overexpression inhibits the growth of NSCLC cells by inducing apoptosis and cell cycle disturbance via the transactivation of c-myc and cyclin D1 through β-catenin/TCF-4 signaling (17). The abovementioned emphasize the tumor suppressive role of Dkk3 with capacities of promoting apoptosis and inhibiting proliferation in lung cancer cells (18). The possible chemosensitizing effect of Dkk3 is suggested as its homologue, Dkk1, has shown a pro-apoptotic activity that inhibits the growth synergistically with cisplatin in cisplatin-resistant head-neck and brain tumor cells (19,20).…”

Section: Introductionmentioning

confidence: 99%

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Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Wang

et al. 2014

Oncology Reports

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Abstract. Previous studies have shown that is inactivated in lung cancer cells, while the inactivation of the Wnt/β-catenin signaling pathway by Dkk3 inhibits lung cancer progression. In the present study, we investigated whether Dkk3 enhances the sensitivity of lung cancer cells to cisplatin. A549, Calu1 and H460 lung adenocarcinoma cell lines were transfected with DKK3 siRNA, while the cisplatin-resistant subline A549cis was transfected with DKK3. DKK3 expression was attenuated in A549cis, Calu1cis and H460cis compared to A549, Calu1 and H460, respectively. Lung adenocarcinoma cell growth, proliferation, apoptosis, cell cycle in vitro and in vivo were then analyzed. DKK3 knockdown by siRNA transfection rendered A549, Calu1 and H460 resistant to cisplatin. As a result of DKK3 transfection, the expression of DKK3 and E-cadherin was significantly upregulated, while that of MMP7, survivin, c-myc and cyclin D1 was downregulated. DKK3 overexpression retarded cell proliferation, induced cell cycle arrest and apoptosis, and reduced cell invasive ability in the A549 and A549cis cells. In addition, the proportions of apoptotic cells and the PARP level were significantly increased in A549cis-and H460cis-DKK3 cells treated with cisplatin. Moreover, tumor growth was retarded more in cisplatin-treated nude mice seeded with A549cis-DKK3 cells than with A549cis cells. Cell viability increased with the pretreatment of SB216763 for 2 h in A549cis and A549cis-DKK3 cells incubated with cisplatin (1 µM) for 72 h. In conclusion, the re-activation of Dkk3 enhances the chemosensitivity to cisplatin in cisplatin-resistant lung adenocarcinoma cell lines, which requires additional studies to realize this potential in clinical use. IntroductionLung cancer has emerged as the third leading cause of cancer-related mortality worldwide (1). In the USA, over 200,000 new lung cancer cases are diagnosed annually, causing over 150,000 deaths in one year (1). Approximately 85% of lung cancer patients suffer from non-small cell lung cancer (NSCLC). Due to the comparative therapeutic advantage, cisplatin-based combination regimens are recommended as the optimal choice currently for the majority of NSCLC patients indicative of chemotherapy or adjuvant chemotherapy (2). However, the average survival time for patients with advanced stage of NSCLC receiving cisplatin plus gemcitabine treatment is ~16 months and may even be reduced to 12 months in those with cisplatin-resistance (3). The dilemma in managing late-stage NSCLC requires the elucidation of the mechanisms in cisplatin resistance to define novel, effective and applicable therapeutic targets for lung cancer (2,3).Several signal transduction pathways controlling chemosensitivity are aberrantly activated in various types of cancer, among which Wnt is of special significance (4). The role of Wnt1/Int-1 in the induction of mouse mammary tumor as an integration site for mouse mammary tumor virus (MMTV) was first recognized 30 years ago (4). Wnt/β-catenin signaling is initiated by the binding of secre...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Wang

et al. 2014

Oncology Reports

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Secreted Wnt Inhibitors or Modulators

Bovolenta

Gorny

Esteve

et al. 2014

WNT Signaling in Development and Disease

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Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration

et al. 2021

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Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of Dkk3 enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, Dkk3-null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5 + liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical-Wnt-signaling in Dkk3-null animals. This results in reduced expression of the Hedgehog repressor Gli3 and increased Hedgehog-signaling activity upon Dkk3 loss. Collectively, these data reveal Dkk3 as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical-Wnt-, and Hedgehog-signaling.

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Targeting the Wnt pathway in cancer: The emerging role of Dickkopf-3

Cited by 147 publications

References 108 publications

Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Secreted Wnt Inhibitors or Modulators

Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration

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