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The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer.
Nat Commun
July 2022
Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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.
View Article and Find Full Text PDFβ-Carotene Oxygenase 2 Genotype Modulates the Impact of Dietary Lycopene on Gene Expression during Early TRAMP Prostate Carcinogenesis.
J Nutr
April 2022
The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Background: Epidemiologic studies suggest lycopene and tomato intake are inversely associated with human prostate cancer incidence. In the genetically driven murine prostate carcinogenesis model transgenic adenocarcinoma of the mouse prostate (TRAMP), prostate cancer is inhibited by feeding of lycopene or tomatoes, and these effects are modulated by the β-carotene oxygenase 2 (Bco2) genotype.
Objective: We sought insight into this interaction through evaluation of prostate gene expression patterns during early TRAMP carcinogenesis.
TASIN (Truncated APC-Selective Inhibitors) compounds are selectively toxic to colorectal cancer cells with mutations, although their mechanism of action remains unknown. Here, we found that TASINs inhibit three enzymes in the postsqualene cholesterol biosynthetic pathway including EBP, DHCR7, and DHCR24. Even though all three of these enzymes are required for cholesterol biosynthesis, only inhibition of the most upstream enzyme, EBP, led to cancer cell death via depletion of downstream sterols, an observation that was confirmed by genetic silencing of EBP.
View Article and Find Full Text PDFAbnormality of intestinal cholesterol absorption in mice with colon cancer cachexia.
Int J Clin Exp Pathol
March 2019
Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University Changchun, Jilin Province, China.
Colorectal cancer syndrome has been one of the greatest concerns in the world, particularly in developed countries. Several epidemiological studies have shown that dyslipidemia may be associated with the progression of intestinal cachexia, but there is little research on the function of the small intestine, which is involved in blood lipid metabolism, in dyslipidemia. In the present study, we aimed to explore the function of intestinal cholesterol absorption in the mouse model using an intestinal lipid absorption test.
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