- Title
- BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma
- Creator
- Liu, Fen; Jiang, Chen Chen; Thorne, Rick F.; Jin, Lei; Wang, Qi; Zhang, Xu Dong; Yan, Xu Guang; Tseng, Hsin-Yi; Wang, Chun Yan; Zhang, Yuan Yuan; Yari, Hamed; La, Ting; Farrelly, Margaret; Guo, Su Tang
- Relation
- Oncotarget Vol. 8, Issue 41, p. 69477-69492
- Publisher Link
- http://dx.doi.org/10.18632/oncotarget.17704
- Publisher
- Impact Journals
- Resource Type
- journal article
- Date
- 2017
- 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.
- Subject
- CD47; BRAF/MEK inhibitors; NRF-1; melanoma; phagocytosis
- Identifier
- http://hdl.handle.net/1959.13/1387004
- Identifier
- uon:32504
- Identifier
- ISSN:1949-2553
- Rights
- This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- Language
- eng
- Full Text
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