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The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer

Therapeutic targeting of KRAS-mutant colorectal cancer (CRC) is an unmet need. Here, we show that Proprotein Convertase Subtilisin/Kexin type 9 (PSCK9) promotes APC/KRAS-mutant CRC and is a therapeutic target. Using CRC patient cohorts, isogenic cell lines and transgenic mice, we identify that de no...

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Autores principales: Wong, Chi Chun, Wu, Jian-Lin, Ji, Fenfen, Kang, Wei, Bian, Xiqing, Chen, Huarong, Chan, Lam-Shing, Luk, Simson Tsz Yat, Tong, Samuel, Xu, Jiaying, Zhou, Qiming, Liu, Dabin, Su, Hao, Gou, Hongyan, Cheung, Alvin Ho-Kwan, To, Ka Fai, Cai, Zongwei, Shay, Jerry W., Yu, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270407/
https://www.ncbi.nlm.nih.gov/pubmed/35803966
http://dx.doi.org/10.1038/s41467-022-31663-z
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author Wong, Chi Chun
Wu, Jian-Lin
Ji, Fenfen
Kang, Wei
Bian, Xiqing
Chen, Huarong
Chan, Lam-Shing
Luk, Simson Tsz Yat
Tong, Samuel
Xu, Jiaying
Zhou, Qiming
Liu, Dabin
Su, Hao
Gou, Hongyan
Cheung, Alvin Ho-Kwan
To, Ka Fai
Cai, Zongwei
Shay, Jerry W.
Yu, Jun
author_facet Wong, Chi Chun
Wu, Jian-Lin
Ji, Fenfen
Kang, Wei
Bian, Xiqing
Chen, Huarong
Chan, Lam-Shing
Luk, Simson Tsz Yat
Tong, Samuel
Xu, Jiaying
Zhou, Qiming
Liu, Dabin
Su, Hao
Gou, Hongyan
Cheung, Alvin Ho-Kwan
To, Ka Fai
Cai, Zongwei
Shay, Jerry W.
Yu, Jun
author_sort Wong, Chi Chun
collection PubMed
description Therapeutic targeting of KRAS-mutant colorectal cancer (CRC) is an unmet need. Here, we show that Proprotein Convertase Subtilisin/Kexin type 9 (PSCK9) promotes APC/KRAS-mutant CRC and is a therapeutic target. Using CRC patient cohorts, isogenic cell lines and transgenic mice, we identify that de novo cholesterol biosynthesis is induced in APC/KRAS mutant CRC, accompanied by increased geranylgeranyl diphosphate (GGPP)─a metabolite necessary for KRAS activation. PCSK9 is the top up-regulated cholesterol-related gene. PCSK9 depletion represses APC/KRAS-mutant CRC cell growth in vitro and in vivo, whereas PCSK9 overexpression induces oncogenesis. Mechanistically, PCSK9 reduces cholesterol uptake but induces cholesterol de novo biosynthesis and GGPP accumulation. GGPP is a pivotal metabolite downstream of PCSK9 by activating KRAS/MEK/ERK signaling. PCSK9 inhibitors suppress growth of APC/KRAS-mutant CRC cells, organoids and xenografts, especially in combination with simvastatin. PCSK9 overexpression predicts poor survival of APC/KRAS-mutant CRC patients. Together, cholesterol homeostasis regulator PCSK9 promotes APC/KRAS-mutant CRC via GGPP-KRAS/MEK/ERK axis and is a therapeutic target.
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spelling pubmed-92704072022-07-10 The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer Wong, Chi Chun Wu, Jian-Lin Ji, Fenfen Kang, Wei Bian, Xiqing Chen, Huarong Chan, Lam-Shing Luk, Simson Tsz Yat Tong, Samuel Xu, Jiaying Zhou, Qiming Liu, Dabin Su, Hao Gou, Hongyan Cheung, Alvin Ho-Kwan To, Ka Fai Cai, Zongwei Shay, Jerry W. Yu, Jun Nat Commun Article Therapeutic targeting of KRAS-mutant colorectal cancer (CRC) is an unmet need. Here, we show that Proprotein Convertase Subtilisin/Kexin type 9 (PSCK9) promotes APC/KRAS-mutant CRC and is a therapeutic target. Using CRC patient cohorts, isogenic cell lines and transgenic mice, we identify that de novo cholesterol biosynthesis is induced in APC/KRAS mutant CRC, accompanied by increased geranylgeranyl diphosphate (GGPP)─a metabolite necessary for KRAS activation. PCSK9 is the top up-regulated cholesterol-related gene. PCSK9 depletion represses APC/KRAS-mutant CRC cell growth in vitro and in vivo, whereas PCSK9 overexpression induces oncogenesis. Mechanistically, PCSK9 reduces cholesterol uptake but induces cholesterol de novo biosynthesis and GGPP accumulation. GGPP is a pivotal metabolite downstream of PCSK9 by activating KRAS/MEK/ERK signaling. PCSK9 inhibitors suppress growth of APC/KRAS-mutant CRC cells, organoids and xenografts, especially in combination with simvastatin. PCSK9 overexpression predicts poor survival of APC/KRAS-mutant CRC patients. Together, cholesterol homeostasis regulator PCSK9 promotes APC/KRAS-mutant CRC via GGPP-KRAS/MEK/ERK axis and is a therapeutic target. Nature Publishing Group UK 2022-07-08 /pmc/articles/PMC9270407/ /pubmed/35803966 http://dx.doi.org/10.1038/s41467-022-31663-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wong, Chi Chun
Wu, Jian-Lin
Ji, Fenfen
Kang, Wei
Bian, Xiqing
Chen, Huarong
Chan, Lam-Shing
Luk, Simson Tsz Yat
Tong, Samuel
Xu, Jiaying
Zhou, Qiming
Liu, Dabin
Su, Hao
Gou, Hongyan
Cheung, Alvin Ho-Kwan
To, Ka Fai
Cai, Zongwei
Shay, Jerry W.
Yu, Jun
The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer
title The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer
title_full The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer
title_fullStr The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer
title_full_unstemmed The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer
title_short The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer
title_sort cholesterol uptake regulator pcsk9 promotes and is a therapeutic target in apc/kras-mutant colorectal cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270407/
https://www.ncbi.nlm.nih.gov/pubmed/35803966
http://dx.doi.org/10.1038/s41467-022-31663-z
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