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BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma

The expression of CD47 on the cancer cell surface transmits “don’t eat me” signalling that not only inhibits phagocytosis of cancer cells by phagocytes but also impairs anti-cancer T cell responses. Here we report that oncogenic activation of ERK plays an important role in transcriptional activation...

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Autores principales: Liu, Fen, Jiang, Chen Chen, Yan, Xu Guang, Tseng, Hsin-Yi, Wang, Chun Yan, Zhang, Yuan Yuan, Yari, Hamed, La, Ting, Farrelly, Margaret, Guo, Su Tang, Thorne, Rick F., Jin, Lei, Wang, Qi, Zhang, Xu Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642493/
https://www.ncbi.nlm.nih.gov/pubmed/29050218
http://dx.doi.org/10.18632/oncotarget.17704
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author Liu, Fen
Jiang, Chen Chen
Yan, Xu Guang
Tseng, Hsin-Yi
Wang, Chun Yan
Zhang, Yuan Yuan
Yari, Hamed
La, Ting
Farrelly, Margaret
Guo, Su Tang
Thorne, Rick F.
Jin, Lei
Wang, Qi
Zhang, Xu Dong
author_facet Liu, Fen
Jiang, Chen Chen
Yan, Xu Guang
Tseng, Hsin-Yi
Wang, Chun Yan
Zhang, Yuan Yuan
Yari, Hamed
La, Ting
Farrelly, Margaret
Guo, Su Tang
Thorne, Rick F.
Jin, Lei
Wang, Qi
Zhang, Xu Dong
author_sort Liu, Fen
collection PubMed
description The expression of CD47 on the cancer cell surface transmits “don’t eat me” signalling that not only inhibits phagocytosis of cancer cells by phagocytes but also impairs anti-cancer T cell responses. Here we report that oncogenic activation of ERK plays an important role in transcriptional activation of CD47 through nuclear respiratory factor 1 (NRF-1) in melanoma cells. Treatment with BRAF/MEK inhibitors upregulated CD47 in cultured melanoma cells and fresh melanoma isolates. Similarly, melanoma cells selected for resistance to the BRAF inhibitor vemurafenib expressed higher levels of CD47. The increase in CD47 expression was mediated by ERK signalling, as it was associated with rebound activation of ERK and co-knockdown of ERK1/2 by siRNA diminished upregulation of CD47 in melanoma cells after exposure to BRAF/MEK inhibitors. Furthermore, ERK1/2 knockdown also reduced the constitutive expression of CD47 in melanoma cells. We identified a DNA fragment that was enriched with the consensus binding sites for NRF-1 and was transcriptionally responsive to BRAF/MEK inhibitor treatment. Knockdown of NRF-1 inhibited the increase in CD47, indicating that NRF-1 has a critical role in transcriptional activation of CD47 by ERK signalling. Functional studies showed that melanoma cells resistant to vemurafenib were more susceptible to macrophage phagocytosis when CD47 was blocked. So these results suggest that NRF-1-mediated regulation of CD47 expression is a novel mechanism by which ERK signalling promotes the pathogenesis of melanoma, and that the combination of CD47 blockade and BRAF/MEK inhibitors may be a useful approach for improving their therapeutic efficacy.
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spelling pubmed-56424932017-10-18 BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma Liu, Fen Jiang, Chen Chen Yan, Xu Guang Tseng, Hsin-Yi Wang, Chun Yan Zhang, Yuan Yuan Yari, Hamed La, Ting Farrelly, Margaret Guo, Su Tang Thorne, Rick F. Jin, Lei Wang, Qi Zhang, Xu Dong Oncotarget Research Paper The expression of CD47 on the cancer cell surface transmits “don’t eat me” signalling that not only inhibits phagocytosis of cancer cells by phagocytes but also impairs anti-cancer T cell responses. Here we report that oncogenic activation of ERK plays an important role in transcriptional activation of CD47 through nuclear respiratory factor 1 (NRF-1) in melanoma cells. Treatment with BRAF/MEK inhibitors upregulated CD47 in cultured melanoma cells and fresh melanoma isolates. Similarly, melanoma cells selected for resistance to the BRAF inhibitor vemurafenib expressed higher levels of CD47. The increase in CD47 expression was mediated by ERK signalling, as it was associated with rebound activation of ERK and co-knockdown of ERK1/2 by siRNA diminished upregulation of CD47 in melanoma cells after exposure to BRAF/MEK inhibitors. Furthermore, ERK1/2 knockdown also reduced the constitutive expression of CD47 in melanoma cells. We identified a DNA fragment that was enriched with the consensus binding sites for NRF-1 and was transcriptionally responsive to BRAF/MEK inhibitor treatment. Knockdown of NRF-1 inhibited the increase in CD47, indicating that NRF-1 has a critical role in transcriptional activation of CD47 by ERK signalling. Functional studies showed that melanoma cells resistant to vemurafenib were more susceptible to macrophage phagocytosis when CD47 was blocked. So these results suggest that NRF-1-mediated regulation of CD47 expression is a novel mechanism by which ERK signalling promotes the pathogenesis of melanoma, and that the combination of CD47 blockade and BRAF/MEK inhibitors may be a useful approach for improving their therapeutic efficacy. Impact Journals LLC 2017-05-09 /pmc/articles/PMC5642493/ /pubmed/29050218 http://dx.doi.org/10.18632/oncotarget.17704 Text en Copyright: © 2017 Liu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Liu, Fen
Jiang, Chen Chen
Yan, Xu Guang
Tseng, Hsin-Yi
Wang, Chun Yan
Zhang, Yuan Yuan
Yari, Hamed
La, Ting
Farrelly, Margaret
Guo, Su Tang
Thorne, Rick F.
Jin, Lei
Wang, Qi
Zhang, Xu Dong
BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma
title BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma
title_full BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma
title_fullStr BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma
title_full_unstemmed BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma
title_short BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma
title_sort braf/mek inhibitors promote cd47 expression that is reversible by erk inhibition in melanoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642493/
https://www.ncbi.nlm.nih.gov/pubmed/29050218
http://dx.doi.org/10.18632/oncotarget.17704
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