ArticleNature communications2022
The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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73 citing papers in PubMed, 90 citations in OpenAlex.
- Metabolic reprogramming in colorectal cancer: Mechanisms and therapeutic insights.Genes & diseases · 2027Review
- Article
- Mutant KRAS-mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Role of PCSK9 in hallmarks of cancer: From mechanisms to interventions (Review).Oncology letters · 2026Review
- KRAS signaling networks, mutational heterogeneity, and emerging therapeutic strategies for cancer treatment.Biomarker research · 2026Review
- Matrix stiffness promotes colorectal cancer progression via Golgi-dependent cholesterol synthesis.Cell death & disease · 2026Article
- Tumor-derived PCSK9-enriched exosomes reprogram adipocytes to drive metabolic dysregulation and immune evasion in triple-negative breast cancer.Cell death & disease · 2026Article
- Revisiting the Lipid-Cancer Axis: PCSK9, ANGPTL3, and CETP as Emerging Biomarkers and Therapeutic Targets in Oncology.Biomolecules · 2026Review
- Genetic attenuation of ALDH1A1 increases metastatic potential and aggressiveness in colorectal cancer.Molecular oncology · 2026Article
- Gender differences in the plasma profiles of proprotein convertase subtilisin/kexin-type 9 (PCSK9), soluble low-density lipoprotein receptor (sLDLR), total cholesterol, and triglycerides in patients with colorectal cancer liver metastases: diagnostic and prognostic implications.Lipids in health and disease · 2026Article
- Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.Cellular & molecular immunology · 2026Review
- Balancing cholesterol metabolism in the liver and gut: perspectives in health and disease.Nature reviews. Gastroenterology & hepatology · 2026Review
- Lipid metabolism as a central driver of immune remodeling and therapeutic vulnerability in metastatic colorectal cancer.Lipids in health and disease · 2026Review
- NAT10 promotes gallbladder cancer progression by remodeling cholesterol metabolism via PCSK9 mRNA acetylation.Cell death discovery · 2026Article
- APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer.Cell reports · 2026Article
- Targeting cholesterol-driven immunometabolism in cancer: from molecular circuits to clinical translation.Molecular cancer · 2026Review
- Interplay Between Gut Microbiota and Cholesterol Metabolism in Colorectal Cancer.International journal of molecular sciences · 2026Review
- β-Hydroxybutyrate, a primary metabolite of ketogenic diets and its dual role in modulating colorectal cancer: from molecular mechanisms to therapeutic insights.Clinical and experimental medicine · 2026Review
- Pan-cancer analysis of cholesterol metabolism reveals the uptake as a modulator of tumor immune features and of the KRAS pathway.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- LAMA1 Promotes Tumor-Associated Macrophages Polarization Towards the M2 Phenotype and Induces Colorectal Cancer.Applied biochemistry and biotechnology · 2026Article
13 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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