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- Title
The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer.
- Authors
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
- Abstract
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. Looking for metabolic-associated vulnerabilities is a promising approach for therapeutic intervention in KRAS-mutant colorectal cancer. Here, the authors show that the cholesterol-uptake regulator PCSK9 drives tumourigenesis and is a therapeutic target in KRASmutant colorectal cancer.
- Subjects
COLORECTAL cancer; CHOLESTEROL; ANTIGEN presenting cells; TRANSGENIC mice; THERAPEUTICS; CELL growth; HYDROXYCHOLESTEROLS
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-31663-z