scholarly journals Update on PCSK9 Inhibitors and New Therapies

2016 ◽  
Vol 12 (01) ◽  
pp. 18
Author(s):  
Evan A Stein ◽  
Frederick J Raal ◽  
◽  
Keyword(s):  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Receptor ◽  
Pcsk9 Inhibitors ◽  
The Us ◽  
Density Lipoprotein Receptor ◽  
Large Phase ◽  
Cutaneous Administration ◽  
Phase Ii And Iii

Proprotein convertase subtilisin/kexin type 9 (PCSK9), first described in 2003, binds to the low-density lipoprotein receptor (LDLR) resulting in its degradation. Inhibition of PCSK9 results in increased LDLR recycling and a reduction in LDL-cholesterol (LDL-C). The clinical development of monoclonal antibodies (mAbs) that bind to circulating PCSK9 has been rapid with large phase II and III trials demonstrating substantial reductions in LDL-C when given to a very broad group of patients including those with familial and non-familial hypercholesterolemia, diabetes, heart disease, and in those intolerant to statins. Despite sub-cutaneous administration these mAbs are well tolerated and have demonstrated good safety. Two agents, alirocumab and evolocumab, received regulatory approval in 2015 in the US and Europe and evolocumab in 2016 in Japan.

scholarly journals Regulation of low-density lipoprotein receptor expression in triple negative breast cancer by EGFR-MAPK signaling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tiffany Scully ◽  
Nathan Kase ◽  
Emily J. Gallagher ◽  
Derek LeRoith
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Tnbc Cell ◽  
Density Lipoprotein Receptor ◽  
Stimulation Of

AbstractExpression of the low-density lipoprotein receptor (LDLR) has been shown to play a critical role in hypercholesterolemia-associated breast cancer growth and is associated with shorter recurrence-free survival in human breast cancer studies. We sought to identify how circulating LDL cholesterol and tumor LDLR might accelerate oncogenic processes by determining whether increased LDLR expression and cholesterol uptake are associated with the activation of the epidermal growth factor receptor (EGFR) signaling pathway in triple negative breast cancer (TNBC) cell lines. EGF stimulation of MDA-MB-468 (MDA468) cells activated p44/42MAPK (MAPK), increased expression of LDLR, and fluorescent LDL cholesterol uptake. However, stimulation of MDA-MB-231 (MDA231) cells with EGF did not lead to increased expression of LDLR despite inducing phosphorylation of EGFR. Inhibition of MAPK using UO126 in MDA231 cells reduced LDLR expression, and in MDA468 cells, UO126 impaired the LDLR increase in response to EGF. MDA468 cells exposed to the transcription inhibitor, Actinomycin, prior to treatment with EGF showed reduced degradation of LDLR mRNA compared to vehicle-treated cells. Our results suggest that the EGF-associated increase in LDLR protein expression is cell line-specific. The common pathway regulating LDLR expression was MAPK in both TNBC cell lines.

scholarly journals Ser-Phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (Family With Sequence Similarity 20, Member C) Kinase Enhances Its Ability to Degrade the LDLR (Low-Density Lipoprotein Receptor)

2019 ◽  
Vol 39 (10) ◽  
pp. 1996-2013 ◽  
Author(s):  
Ali Ben Djoudi Ouadda ◽  
Marie-Soleil Gauthier ◽  
Delia Susan-Resiga ◽  
Emmanuelle Girard ◽  
Rachid Essalmani ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Sequence Similarity ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Regulation Mechanism ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Proprotein Convertase ◽  
Low Density Lipoprotein Receptor ◽  
Density Lipoprotein Receptor

Objective: PCSK9 (proprotein convertase subtilisin-kexin 9) enhances the degradation of the LDLR (low-density lipoprotein receptor) in endosomes/lysosomes. This study aimed to determine the sites of PCSK9 phosphorylation at Ser-residues and the consequences of such posttranslational modification on the secretion and activity of PCSK9 on the LDLR. Approach and Results: Fam20C (family with sequence similarity 20, member C) phosphorylates serines in secretory proteins containing the motif S-X-E/phospho-Ser, including the cholesterol-regulating PCSK9. In situ hybridization of Fam20C mRNA during development and in adult mice revealed a wide tissue distribution, including liver, but not small intestine. Here, we show that Fam20C phosphorylates PCSK9 at Serines 47, 666, 668, and 688. In hepatocytes, phosphorylation enhances PCSK9 secretion and maximizes its induced degradation of the LDLR via the extracellular and intracellular pathways. Replacing any of the 4 Ser by the phosphomimetic Glu or Asp enhanced PCSK9 activity only when the other sites are phosphorylated, whereas Ala substitutions reduced it, as evidenced by Western blotting, Elisa, and LDLR-immunolabeling. This newly uncovered PCSK9/LDLR regulation mechanism refines our understanding of the implication of global PCSK9 phosphorylation in the modulation of LDL-cholesterol and rationalizes the consequence of natural mutations, for example, S668R and E670G. Finally, the relationship of Ser-phosphorylation to the implication of PCSK9 in regulating LDL-cholesterol in the neurological Fragile X-syndrome disorder was investigated. Conclusions: Ser-phosphorylation of PCSK9 maximizes both its secretion and activity on the LDLR. Mass spectrometric approaches to measure such modifications were developed and applied to quantify the levels of bioactive PCSK9 in human plasma under normal and pathological conditions.

Sign in / Sign up

Export Citation Format

Share Document