Fig. 5: PCSK9 promotes APC/KRAS-mutant CRC growth in vivo and growth inhibitory effect of PCSK9 inhibitors.

A PCSK9 knockout suppressed growth of subcutaneous xenograft model of SW1116 cells in NOD/SCID mice (n = 1 experiment, n = 9 mice per group). B PCSK9 knockout inhibited cell growth as indicated by Ki-67 staining (n = 5); TUNEL showed that PCSK9 knockout induced apoptosis in SW1116 xenografts (n = 5). C PCSK9 overexpression in DLD1 cells induced xenograft growth in nude mice (n = 1 experiment, n = 10 mice per group). D PCSK9 overexpression in DLD1 cells induced cell growth and inhibited apoptosis, as evidenced by Ki-67 (n = 7) and TUNEL (n = 8) assays, respectively. E Western blot of SW1116 xenografts revealed that PCSK9 knockout suppressed p-ERK, Cyclin D1, and CDK4. Western blot of DLD1 xenografts demonstrated increased expression of p-ERK, Cyclin D1, and CDK4. F GGPP levels in SW116 xenografts with PCSK9 knockout (n = 8) and DLD1 xenografts with PCSK9 overexpression (n = 10). G Effect of Evolocumab on 1CT, 1CT-AK, and DLD1 cells (n = 3). H Effect of R-IMPP and PF-0644846 on 1CT, 1CT-AK, and DLD1 cells (n = 3). 72 h-IC₅₀ values of R-IMPP and PF-0644846 in a panel of APC/KRAS mutant CRC, 1CT isogenic cells and NCM460 cells. I Effect of Evolocumab, R-IMPP, and PF-0644846 on cell viability of primary organoids from human APC/ KRAS-mutant CRC after 5–7 days of treatment (n = 4). J Effect of Evolocumab, R-IMPP and PF-0644846 on cholesterol gene expression in KRAS-mutant CRC organoids (n = 3) after 72 h of drug treatment. Data shown are means of biological replicates; ± SEM (A–D, F, G–J). Two-tailed Student’s t-test (A–D, F, G, I, J). Two-tailed two-way ANOVA for growth curves (a, c). Source data are provided as a Source Data file.