Proprotein Convertase Subtilisin/Kexin Type 9 Deficiency Reduces Melanoma Metastasis in Liver
High circulating cholesterol is associated with hypercholesterolemia, atherosclerosis, and stroke. However, the relation between cholesterol and tumorigenesis/metastasis is controversial. The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein cholesterol homeost...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2012-12-01
|
Series: | Neoplasia: An International Journal for Oncology Research |
Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558612800492 |
id |
doaj-92c2cd84c71e4196a4412f95f41963ae |
---|---|
record_format |
Article |
spelling |
doaj-92c2cd84c71e4196a4412f95f41963ae2020-11-24T22:40:37ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022012-12-0114121122113110.1593/neo.121252Proprotein Convertase Subtilisin/Kexin Type 9 Deficiency Reduces Melanoma Metastasis in LiverXiaowei Sun0Rachid Essalmani1Robert Day2Abdel M. Khatib3Nabil G. Seidah4Annik Prat5Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, QC, CanadaLaboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, QC, CanadaInstitut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, CanadaINSERM U1029, Université Bordeaux 1, Talence, FranceLaboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, QC, CanadaLaboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, QC, Canada High circulating cholesterol is associated with hypercholesterolemia, atherosclerosis, and stroke. However, the relation between cholesterol and tumorigenesis/metastasis is controversial. The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein cholesterol homeostasis by targeting the low-density lipoprotein receptor (LDLR) for degradation. PCSK9 is mostly expressed in liver, which is one of the most common sites for metastatic disease. To reveal the function of PCSK9 and also evaluate the impact of cholesterol in liver metastasis development, B16F1 melanoma cells were injected into wild-type (WT) and Pcsk9-/- mice to induce liver metastasis. On chow diet, Pcsk9-/- mice harbored two-fold less liver metastases than WT mice. This decrease is related to low cholesterol levels in Pcsk9-/- mice, as the protection was lost after normalizing Pcsk9-/- cholesterol levels by a 2-week high cholesterol diet. Furthermore, a prolongation of this diet strongly increased metastasis in both genotypes, suggesting that high cholesterol levels promote metastatic progression. The protective effect of the PCSK9 deficiency is also associated with increased apoptosis in liver stroma and metastases. Tumor necrosis factor.α (TNFα) mRNA and protein were, respectively, higher in liver stroma and plasma of injected mice, likely increasing the apoptotic TNFα signaling. Furthermore, the anti-apoptotic factor B-cell lymphoma 2 was downregulated. TNFα regulation is LDLR-independent, as its mRNA level was similarly upregulated in mice lacking both PCSK9 and LDLR. Our findings show that PCSK9 deficiency reduces liver metastasis by its ability to lower cholesterol levels and by possibly enhancing TNFα-mediated apoptosis. http://www.sciencedirect.com/science/article/pii/S1476558612800492 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiaowei Sun Rachid Essalmani Robert Day Abdel M. Khatib Nabil G. Seidah Annik Prat |
spellingShingle |
Xiaowei Sun Rachid Essalmani Robert Day Abdel M. Khatib Nabil G. Seidah Annik Prat Proprotein Convertase Subtilisin/Kexin Type 9 Deficiency Reduces Melanoma Metastasis in Liver Neoplasia: An International Journal for Oncology Research |
author_facet |
Xiaowei Sun Rachid Essalmani Robert Day Abdel M. Khatib Nabil G. Seidah Annik Prat |
author_sort |
Xiaowei Sun |
title |
Proprotein Convertase Subtilisin/Kexin Type 9 Deficiency Reduces Melanoma Metastasis in Liver |
title_short |
Proprotein Convertase Subtilisin/Kexin Type 9 Deficiency Reduces Melanoma Metastasis in Liver |
title_full |
Proprotein Convertase Subtilisin/Kexin Type 9 Deficiency Reduces Melanoma Metastasis in Liver |
title_fullStr |
Proprotein Convertase Subtilisin/Kexin Type 9 Deficiency Reduces Melanoma Metastasis in Liver |
title_full_unstemmed |
Proprotein Convertase Subtilisin/Kexin Type 9 Deficiency Reduces Melanoma Metastasis in Liver |
title_sort |
proprotein convertase subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 1522-8002 |
publishDate |
2012-12-01 |
description |
High circulating cholesterol is associated with hypercholesterolemia, atherosclerosis, and stroke. However, the relation between cholesterol and tumorigenesis/metastasis is controversial. The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein cholesterol homeostasis by targeting the low-density lipoprotein receptor (LDLR) for degradation. PCSK9 is mostly expressed in liver, which is one of the most common sites for metastatic disease. To reveal the function of PCSK9 and also evaluate the impact of cholesterol in liver metastasis development, B16F1 melanoma cells were injected into wild-type (WT) and Pcsk9-/- mice to induce liver metastasis. On chow diet, Pcsk9-/- mice harbored two-fold less liver metastases than WT mice. This decrease is related to low cholesterol levels in Pcsk9-/- mice, as the protection was lost after normalizing Pcsk9-/- cholesterol levels by a 2-week high cholesterol diet. Furthermore, a prolongation of this diet strongly increased metastasis in both genotypes, suggesting that high cholesterol levels promote metastatic progression. The protective effect of the PCSK9 deficiency is also associated with increased apoptosis in liver stroma and metastases. Tumor necrosis factor.α (TNFα) mRNA and protein were, respectively, higher in liver stroma and plasma of injected mice, likely increasing the apoptotic TNFα signaling. Furthermore, the anti-apoptotic factor B-cell lymphoma 2 was downregulated. TNFα regulation is LDLR-independent, as its mRNA level was similarly upregulated in mice lacking both PCSK9 and LDLR. Our findings show that PCSK9 deficiency reduces liver metastasis by its ability to lower cholesterol levels and by possibly enhancing TNFα-mediated apoptosis.
|
url |
http://www.sciencedirect.com/science/article/pii/S1476558612800492 |
work_keys_str_mv |
AT xiaoweisun proproteinconvertasesubtilisinkexintype9deficiencyreducesmelanomametastasisinliver AT rachidessalmani proproteinconvertasesubtilisinkexintype9deficiencyreducesmelanomametastasisinliver AT robertday proproteinconvertasesubtilisinkexintype9deficiencyreducesmelanomametastasisinliver AT abdelmkhatib proproteinconvertasesubtilisinkexintype9deficiencyreducesmelanomametastasisinliver AT nabilgseidah proproteinconvertasesubtilisinkexintype9deficiencyreducesmelanomametastasisinliver AT annikprat proproteinconvertasesubtilisinkexintype9deficiencyreducesmelanomametastasisinliver |
_version_ |
1725704222033313792 |