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Activation of sterol regulatory element‐binding protein 1 (SREBP1)‐mediated lipogenesis by the Epstein–Barr virus‐encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein–Barr virus (EBV) infection. The EBV‐encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation, and metabolic reprogramming. Here, we repo...

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Autores principales: Lo, Angela Kwok‐Fung, Lung, Raymond Wai‐Ming, Dawson, Christopher W, Young, Lawrence S, Ko, Chuen‐Wai, Yeung, Walter Wai, Kang, Wei, To, Ka‐Fai, Lo, Kwok‐Wai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175466/
https://www.ncbi.nlm.nih.gov/pubmed/29968360
http://dx.doi.org/10.1002/path.5130
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author Lo, Angela Kwok‐Fung
Lung, Raymond Wai‐Ming
Dawson, Christopher W
Young, Lawrence S
Ko, Chuen‐Wai
Yeung, Walter Wai
Kang, Wei
To, Ka‐Fai
Lo, Kwok‐Wai
author_facet Lo, Angela Kwok‐Fung
Lung, Raymond Wai‐Ming
Dawson, Christopher W
Young, Lawrence S
Ko, Chuen‐Wai
Yeung, Walter Wai
Kang, Wei
To, Ka‐Fai
Lo, Kwok‐Wai
author_sort Lo, Angela Kwok‐Fung
collection PubMed
description Nasopharyngeal carcinoma (NPC) is closely associated with Epstein–Barr virus (EBV) infection. The EBV‐encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation, and metabolic reprogramming. Here, we report a novel function of LMP1 in promoting de novo lipogenesis. LMP1 increases the expression, maturation and activation of sterol regulatory element‐binding protein 1 (SREBP1), a master regulator of lipogenesis, and its downstream target fatty acid synthase (FASN). LMP1 also induces de novo lipid synthesis and lipid droplet formation. In contrast, small interfering RNA (siRNA) knockdown of LMP1 in EBV‐infected epithelial cells diminished SREBP1 activation and lipid biosynthesis. Furthermore, inhibition of the mammalian target of rapamycin (mTOR) pathway, through the use of either mTOR inhibitors or siRNAs, significantly reduced LMP1‐mediated SREBP1 activity and lipogenesis, indicating that LMP1 activation of the mTOR pathway is required for SREBP1‐mediated lipogenesis. In primary NPC tumors, FASN overexpression is common, with high levels correlating significantly with LMP1 expression. Moreover, elevated FASN expression was associated with aggressive disease and poor survival in NPC patients. Luteolin and fatostatin, two inhibitors of lipogenesis, suppressed lipogenesis and proliferation of nasopharyngeal epithelial cells, effects that were more profound in cells expressing LMP1. Luteolin and fatostatin also dramatically inhibited NPC tumor growth in vitro and in vivo. Our findings demonstrate that LMP1 activation of SREBP1‐mediated lipogenesis promotes tumor cell growth and is involved in EBV‐driven NPC pathogenesis. Our results also reveal the therapeutic potential of utilizing lipogenesis inhibitors in the treatment of locally advanced or metastatic NPC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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spelling pubmed-61754662018-10-19 Activation of sterol regulatory element‐binding protein 1 (SREBP1)‐mediated lipogenesis by the Epstein–Barr virus‐encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma Lo, Angela Kwok‐Fung Lung, Raymond Wai‐Ming Dawson, Christopher W Young, Lawrence S Ko, Chuen‐Wai Yeung, Walter Wai Kang, Wei To, Ka‐Fai Lo, Kwok‐Wai J Pathol Original Papers Nasopharyngeal carcinoma (NPC) is closely associated with Epstein–Barr virus (EBV) infection. The EBV‐encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation, and metabolic reprogramming. Here, we report a novel function of LMP1 in promoting de novo lipogenesis. LMP1 increases the expression, maturation and activation of sterol regulatory element‐binding protein 1 (SREBP1), a master regulator of lipogenesis, and its downstream target fatty acid synthase (FASN). LMP1 also induces de novo lipid synthesis and lipid droplet formation. In contrast, small interfering RNA (siRNA) knockdown of LMP1 in EBV‐infected epithelial cells diminished SREBP1 activation and lipid biosynthesis. Furthermore, inhibition of the mammalian target of rapamycin (mTOR) pathway, through the use of either mTOR inhibitors or siRNAs, significantly reduced LMP1‐mediated SREBP1 activity and lipogenesis, indicating that LMP1 activation of the mTOR pathway is required for SREBP1‐mediated lipogenesis. In primary NPC tumors, FASN overexpression is common, with high levels correlating significantly with LMP1 expression. Moreover, elevated FASN expression was associated with aggressive disease and poor survival in NPC patients. Luteolin and fatostatin, two inhibitors of lipogenesis, suppressed lipogenesis and proliferation of nasopharyngeal epithelial cells, effects that were more profound in cells expressing LMP1. Luteolin and fatostatin also dramatically inhibited NPC tumor growth in vitro and in vivo. Our findings demonstrate that LMP1 activation of SREBP1‐mediated lipogenesis promotes tumor cell growth and is involved in EBV‐driven NPC pathogenesis. Our results also reveal the therapeutic potential of utilizing lipogenesis inhibitors in the treatment of locally advanced or metastatic NPC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. John Wiley & Sons, Ltd 2018-08-22 2018-10 /pmc/articles/PMC6175466/ /pubmed/29968360 http://dx.doi.org/10.1002/path.5130 Text en © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Papers
Lo, Angela Kwok‐Fung
Lung, Raymond Wai‐Ming
Dawson, Christopher W
Young, Lawrence S
Ko, Chuen‐Wai
Yeung, Walter Wai
Kang, Wei
To, Ka‐Fai
Lo, Kwok‐Wai
Activation of sterol regulatory element‐binding protein 1 (SREBP1)‐mediated lipogenesis by the Epstein–Barr virus‐encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma
title Activation of sterol regulatory element‐binding protein 1 (SREBP1)‐mediated lipogenesis by the Epstein–Barr virus‐encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma
title_full Activation of sterol regulatory element‐binding protein 1 (SREBP1)‐mediated lipogenesis by the Epstein–Barr virus‐encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma
title_fullStr Activation of sterol regulatory element‐binding protein 1 (SREBP1)‐mediated lipogenesis by the Epstein–Barr virus‐encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma
title_full_unstemmed Activation of sterol regulatory element‐binding protein 1 (SREBP1)‐mediated lipogenesis by the Epstein–Barr virus‐encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma
title_short Activation of sterol regulatory element‐binding protein 1 (SREBP1)‐mediated lipogenesis by the Epstein–Barr virus‐encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma
title_sort activation of sterol regulatory element‐binding protein 1 (srebp1)‐mediated lipogenesis by the epstein–barr virus‐encoded latent membrane protein 1 (lmp1) promotes cell proliferation and progression of nasopharyngeal carcinoma
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175466/
https://www.ncbi.nlm.nih.gov/pubmed/29968360
http://dx.doi.org/10.1002/path.5130
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