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. 2022 Jul 8;13:3971. doi: 10.1038/s41467-022-31663-z

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© The Author(s) 2022

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/.

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Fig. 6 — A Nude mice harboring SW1116 xenografts were treated with vehicle (PBS), R-IMPP (100 mg/kg), or PF-06446846 (50 mg/kg) (n = 1 experiment, n = 5 mice per group) by intraperitoneal injection every 2 days. Both R-IMPP and PF-06446846 inhibited tumor growth. B siPCSK9 synergized with simvastatin to inhibit cell growth and induce apoptosis of 1CT-AK cells (n = 3, 72 h). C Evolocumab synergized with simvastatin to promote cell apoptosis in KRAS-mutant CRC cells (96 h). D The co-administration of R-IMPP or PF-0644846 reduced 48 h-IC₅₀ of simvastatin in KRAS-mutant CRC cells (left) (n = 3). Isobologram analyses indicated that combination of R-IMPP or PF-0644846 plus simvastatin were synergistic in suppressing cell viability (right). E Nude mice harboring SW1116 xenografts were treated with vehicle, R-IMPP, simvastatin, or their combination (n = 1 experiment, n = 5 mice per group). The combination drug treatment induced tumor regression and significantly suppressed tumor weight, PCSK9 protein expression and GGPP levels compared to vehicle or single treatment. F PCSK9 mRNA is up-regulated in CRC tissues as compared with paired adjacent normal tissues in Hong Kong (n = 150 pairs), and TCGA cohorts (n = 50 pairs), and in unpaired samples from TCGA cohort (n = 675). G PCSK9 protein expression is increased in CRC compared to adjacent normal tissues assessed by western blot. H Tissue microarray cohort (n = 137) showed that PCSK9 protein expression predicts poor survival of APC^MUTKRAS^MUT CRC (n = 66), but not in APC^MUTKRAS^WT CRC (n = 71) or overall cohort. Log-rank test (two-tailed). I PCSK9 mRNA predicts poor patient survival in APC^MUTKRAS^MUT CRC (n = 162) in TCGA cohort, but not in APC^MUTKRAS^WT CRC (n = 206) or overall cohort (n = 368). Log-rank test (two-tailed). J Multivariate COX proportional hazards regression analysis of the prognostic value of PCSK9 in APC^MUTKRAS^MUT CRC patients in both Hong Kong and TCGA cohorts (n = 162, biological replicates). COX proportional hazards regression analysis. Data shown are means of biological replicates; ± SEM (A–F). Two-tailed Student’s t-test (A, E, F). Two-tailed two-way ANOVA for growth curves (A, E). Source data are provided as a Source Data file.