Combination therapy targeting the elevated interleukin-6 level reduces invasive migration of BRAF inhibitor-resistant melanoma cells
(2019) In Molecular Oncology 13(2). p.480-494- Abstract
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... (More)
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.
(Less)
- author
- Mohapatra, Purusottam LU ; Prasad, Chandra Prakash LU and Andersson, Tommy LU
- organization
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- BRAF inhibitor-resistant, interleukin-6, invasion, melanoma, migration, WNT5A
- in
- Molecular Oncology
- volume
- 13
- issue
- 2
- pages
- 480 - 494
- publisher
- Elsevier
- external identifiers
-
- pmid:30582770
- scopus:85059846641
- ISSN
- 1574-7891
- DOI
- 10.1002/1878-0261.12433
- language
- English
- LU publication?
- yes
- id
- 5e2e3442-3616-40c8-bd8d-ab1ad084b734
- date added to LUP
- 2019-01-23 14:18:17
- date last changed
- 2024-06-25 05:01:35
@article{5e2e3442-3616-40c8-bd8d-ab1ad084b734,
abstract = {{<p>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.</p>}},
author = {{Mohapatra, Purusottam and Prasad, Chandra Prakash and Andersson, Tommy}},
issn = {{1574-7891}},
keywords = {{BRAF inhibitor-resistant; interleukin-6; invasion; melanoma; migration; WNT5A}},
language = {{eng}},
number = {{2}},
pages = {{480--494}},
publisher = {{Elsevier}},
series = {{Molecular Oncology}},
title = {{Combination therapy targeting the elevated interleukin-6 level reduces invasive migration of BRAF inhibitor-resistant melanoma cells}},
url = {{http://dx.doi.org/10.1002/1878-0261.12433}},
doi = {{10.1002/1878-0261.12433}},
volume = {{13}},
year = {{2019}},
}