Demonstration of a WNT5A-IL-6 positive feedback loop in melanoma cells: Dual interference of this loop more effectively impairs melanoma cell invasion

Linnskog, Rickard; Mohapatra, Purusottam; Moradi, Farnaz; Prasad, Chandra Prakash; Andersson, Tommy

doi:10.18632/oncotarget.9332

Cited by 26 publications

(22 citation statements)

References 27 publications

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“…We have previously reported the existence of an IL‐6/WNT5A positive feedback loop in parental BRAFi‐sensitive melanoma cells that is related to their migratory and invasive properties (Linnskog et al ., ). The above findings of a parallel increase in WNT5A expression and IL‐6 secretion are in good agreement with such an IL‐6/WNT5A feedback loop also in BRAFi‐R melanoma cells.…”

Section: Resultsmentioning

confidence: 97%

“…Our observation of elevated IL‐6 secretion is in accordance with the observation that IL‐6 is not only a promoter of melanoma metastasis (Na et al ., ) but also an inducer of WNT5A protein expression in parental BRAFi‐sensitive melanoma cells (Linnskog et al ., ). Furthermore, an IL‐6/WNT5A positive feedback loop has been previously shown to be associated with the increased invasive migration of parental BRAFi‐sensitive melanoma cells (Linnskog et al ., ). However, in contrast to this latter finding, we found that the IL‐6/WNT5A positive feedback loop is absent in BRAFi‐R melanoma cells.…”

Section: Discussionmentioning

confidence: 97%

“…This is an interesting observation since IL‐6 has been previously shown to drive melanoma metastasis via its ability to promote melanoma cell invasion (Kushiro et al ., ; Na et al ., ). Furthermore, in a more recent report, we demonstrated that IL‐6 and WNT5A signalling constitute a positive feedback loop that potentiates the migration and invasion of melanoma cells (Linnskog et al ., ).…”

Section: Introductionmentioning

confidence: 97%

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Combination therapy targeting the elevated interleukin‐6 level reduces invasive migration of BRAF inhibitor‐resistant melanoma cells

2019

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The identification of novel antimetastatic therapeutic targets is necessary for improved treatment of patients with acquired BRAF inhibitor‐resistant (BRAFi‐R) melanoma, in whom metastasis is a major concern. Our present study focused on the identification of such targets to explore novel antimetastatic therapeutic options for BRAFi‐R melanoma patients. We confirmed the development of BRAFi resistance in our BRAFi‐treated melanoma cell lines by demonstrating reduced sensitivity to BRAF inhibitors, increased ERK1/2 activity and increased WNT5A expression. Here, we demonstrated for the first time that high secretion of interleukin‐6 (IL‐6) was associated with increased invasive migration of BRAFi‐R melanoma cells. This finding could be readily explained by the increased expression of WNT5A in BRAFi‐R melanoma cells and the presence of an IL‐6/WNT5A positive feedback loop in parental melanoma cells. Surprisingly, however, we found that the IL‐6/WNT5A positive feedback loop present in parental melanoma cells was lost during the development of acquired BRAFi resistance, meaning that IL‐6 and WNT5A signalling were independent events in BRAFi‐R melanoma cells. Despite the absence of an IL‐6/WNT5A loop, we found that both an IL‐6 blocking antibody and the WNT5A antagonist Box5 alone impaired the elevated invasive migration of BRAFi‐R melanoma cells, but combined use of the two was more effective. This impaired invasive migration of BRAFi‐R melanoma cells correlated well with the reduction in Cdc42‐GTPase activity and alterations of the actin cytoskeleton in these cells. In summary, our novel identification of IL‐6 as a key independent promoter of the invasive migration of BRAFi‐R melanoma cells stresses that a combination of a blocking IL‐6 antibody and administration of the WNT5A antagonist Box5 might be an attractive antimetastatic approach for future treatment of BRAFi‐R melanoma patients.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

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Combination therapy targeting the elevated interleukin‐6 level reduces invasive migration of BRAF inhibitor‐resistant melanoma cells

2019

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“…In mice, IL-6 regulates gut epithelial crypt homeostasis through the Wnt signalling pathway [41]. In humans, there is a positive feedback loop between IL-6 and WNT5A in melanoma cells [42], and WNT5A-FZD4/LRP5 signaling support self-renewal of embryonic stem cells [43] and eMSCs [9].…”

Section: Discussionmentioning

confidence: 99%

Understanding the Regulatory Mechanisms of Endometrial Cells on Activities of Endometrial Mesenchymal Stem-Like Cells During Menstruation

Chan

et al. 2020

Preprint

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Background: The identification of endometrial stem/progenitor cells in a high turnover rate tissue suggests that a well-orchestrated underlying network controls the behaviour of these stem cells. The thickness of the endometrium can grow from 0.5 – 1 mm to 5 – 7 mm within a week indicating the need of stem cells for self-renewal and differentiation during this period. The cyclical regeneration of the endometrium suggests specific signals can activate the stem cells during or shortly after menstruation. Methods: Endometrial mesenchymal stem-like cells (eMSCs) were cocultured with endometrial epithelial or stromal cells from different phases of the menstrual cycle, the clonogenicity and the phenotypic expression of eMSC markers (CD140b and CD146) were assessed. The functional role of WNT/β-catenin signalling on eMSC was determined by Western blot analysis, immunofluorecent staining, flow cytometry, quantitative real-time PCR and small interfering RNA. The cytokine levels in the conditioned medium of epithelial or stromal cells cocultured with eMSCs was evaluated by enzyme-linked immunosorbent assays. Results: Coculture of endometrial cells (epithelial or stromal) from the menstrual phase enhanced the clonogenicity and self-renewal activities of eMSCs. Such phenomenon was not observed in niche cells from the proliferative phase. Coculture with endometrial cells from the menstrual phase confirmed an increase in expression of active β-catenin in the eMSCs. Treatment with IWP-2, a WNT inhibitor suppressed the observed effects. Anti-R-spondin-1 antibody reduced the stimulatory action of endometrial niche cells on WNT/β-catenin activation in the T-cell factor/lymphoid enhancer-binding factor luciferase reporter assay. Moreover, the mRNA level and protein immunoreactivities of leucine-rich repeat-containing G-protein coupled receptor 5 were higher in eMSCs than unfractionated stromal cells. Conditioned media of endometrial niche cells cocultured with eMSCs contained increased levels of C-X-C motif ligand 1 (CXCL1), CXCL5 and interleukin 6. Treatment with these cytokines increased the clonogenic activity and phenotypic expression of eMSCs. Conclusions: Our findings indicate a role of WNT/β-catenin signalling in regulating activities of endometrial stem/progenitor cells during menstruation. Certain cytokines at menstruation can stimulate the proliferation and self-renewal activities of eMSCs. Understanding the mechanism in the regulation of eMSCs may contribute to treatments of endometrial proliferative disorders such as Asherman’s Syndrome.

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“…WNT5A modulates melanoma cell behavior via multiple cell surface receptors/co-receptors, including ROR2 [9] and Frizzleds [10], and downstream molecular targets, such as APT1 [11], IL-6 [12], and PKC-STAT3 [13], which in turn affect various melanoma cell functions, including migration and invasion. One clear example of the essential role of WNT5A signaling in melanoma cell dissemination is the observation that simultaneous inhibition of WNT5A expression (with an anti-IL-6 antibody) and downstream WNT5A signaling (with the WNT5A antagonistic peptide Box5) effectively impairs melanoma cell migration and invasion [12]. An important pathway that has been shown to be crucial for WNT5A-mediated melanoma invasion and metastasis is the protein kinase C (PKC) signaling pathway, as demonstrated in several studies by Weeraratna and coworkers [8,9,14].…”

Section: Introductionmentioning

confidence: 99%

WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion

Mohapatra

Yadav

Toftdahl

et al. 2020

Cancers

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WNT5A is a well-known mediator of melanoma cell invasion and metastasis via its ability to activate protein kinase C (PKC), which is monitored by phosphorylation of the endogenous PKC substrate myristoylated alanine-rich c-kinase substrate (MARCKS). However, a possible direct contribution of MARCKS in WNT5A-mediated melanoma cell invasion has not been investigated. Analyses of melanoma patient databases suggested that similar to WNT5A expression, MARCKS expression appears to be associated with increased metastasis. A relationship between the two is suggested by the findings that recombinant WNT5A (rWNT5A) induces both increased expression and phosphorylation of MARCKS, whereas WNT5A silencing does the opposite. Moreover, WNT5A-induced invasion of melanoma cells was blocked by siRNA targeting MARCKS, indicating a crucial role of MARCKS expression and/or its phosphorylation. Next, we employed a peptide inhibitor of MARCKS phosphorylation that did not affect MARCKS expression and found that it abolished WNT5A-induced melanoma cell invasion. Similarly, rWNT5A induced the accumulation of phosphorylated MARCKS in membrane protrusions at the leading edge of melanoma cells. Our results demonstrate that WNT5A-induced phosphorylation of MARCKS is not only an indicator of PKC activity but also a crucial regulator of the metastatic behavior of melanoma and therefore an attractive future antimetastatic target in melanoma patients.

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Demonstration of a WNT5A-IL-6 positive feedback loop in melanoma cells: Dual interference of this loop more effectively impairs melanoma cell invasion

Cited by 26 publications

References 27 publications

Combination therapy targeting the elevated interleukin‐6 level reduces invasive migration of BRAF inhibitor‐resistant melanoma cells

Combination therapy targeting the elevated interleukin‐6 level reduces invasive migration of BRAF inhibitor‐resistant melanoma cells

Understanding the Regulatory Mechanisms of Endometrial Cells on Activities of Endometrial Mesenchymal Stem-Like Cells During Menstruation

WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion

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