Fig. 3: PCSK9 activates de novo cholesterol biosynthesis and GGPP accumulation to promote cell growth. | Nature Communications

Fig. 3: PCSK9 activates de novo cholesterol biosynthesis and GGPP accumulation to promote cell growth.

From: The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer

Fig. 3

A mRNA expression of SREBF2 and cholesterol biosynthesis genes was decreased in PCSK9 knockdown 1CT-AK cells and PCSK9 knockout SW1116 cells (n = 3). B Ectopic expression of PCSK9 in DLD1 cells promoted SREBP2 and cholesterol biosynthesis genes mRNA expression (n = 3). C Western blot showed that PCSK9 knockdown or knockout reduced protein expression of SERBP2 (mature form), HMGCR, and SQLE in 1CT-AK, LOVO, and SW1116 cells; PCSK9 overexpression in DLD1 cells exerted an opposite effect. D R-IMPP and PF-0644846, inhibitors of PCSK9, suppressed expression of SREBP2, HMGCR, and SQLE in APC/KRAS-mutant CRC cell lines. E D2O-labeling (48 h) and LC-MS analysis of intracellular cholesterol demonstrated that PCSK9 depletion inhibited de novo cholesterol biosynthesis in 1CT-AK (n = 4) and SW1116 cells (n = 3), while PCSK9 overexpression promoted de novo cholesterol biosynthesis in DLD1 cells (n = 2). F PCSK9 depletion reduced HMG-CoA, GPP, FPP and GGPP levels in 1CT-AK cells (n = 4), while PCSK9 overexpression increased GPP, FPP and GGPP in DLD1 cells (n = 4). G GGPS1 knockdown (n = 3, 72 h) abrogated growth inducing effect of PCSK9 overexpression in DLD1 cells. H Effect of cholesterol and intermediary metabolites in rescuing the proliferation of PCSK9 knockout SW1116 (n = 4) and LOVO (n = 3) cells. Data shown are means of biological replicates; ± SEM (A, B, E–H). Two-tailed Student’s t-test (A, B, E–H). Source data are provided as a Source Data file.

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