scholarly journals Uptake of high-density lipoprotein by scavenger receptor class B type 1 is associated with prostate cancer proliferation and tumor progression in mice

2020 ◽  
Vol 295 (24) ◽  
pp. 8252-8261 ◽  
Author(s):  
C. Alicia Traughber ◽  
Emmanuel Opoku ◽  
Gregory Brubaker ◽  
Jennifer Major ◽  
Hanxu Lu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Prostate Cancer Cell ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Prostate Cancer Cells ◽  
Scavenger Receptor Class ◽  
Class B

High-density lipoprotein (HDL) metabolism is facilitated in part by scavenger receptor class B, type 1 (SR-B1) that mediates HDL uptake into cells. Higher levels of HDL have been associated with protection in other diseases, however, its role in prostate cancer is not definitive. SR-B1 is up-regulated in prostate cancer tissue, suggesting a possible role of this receptor in tumor progression. Here, we report that knockout (KO) of SR-B1 in both human and mouse prostate cancer cell lines through CRISPR/Cas9-mediated genome editing reduces HDL uptake into the prostate cancer cells and reduces their proliferation in response to HDL. In vivo studies using syngeneic SR-B1 WT (SR-B1+/+) and SR-B1 KO (SR-B1−/−) prostate cancer cells in WT and apolipoprotein-AI KO (apoA1-KO) C57BL/6J mice revealed that WT hosts, containing higher levels of total and HDL-cholesterol, grew larger tumors than apoA1-KO hosts with lower levels of total and HDL-cholesterol. Furthermore, SR-B1−/− prostate cancer cells formed smaller tumors in WT hosts than SR-B1+/+ cells in the same host model. Increased tumor volume was overall associated with reduced survival. We conclude that knocking out SR-B1 in prostate cancer tumors reduces HDL-associated increases in prostate cancer cell proliferation and disease progression.

scholarly journals SR-B1 uptake of HDL promotes prostate cancer proliferation and tumor progression

2020 ◽  
Author(s):  
C. Alicia Traughber ◽  
Emmanuel Opoku ◽  
Gregory Brubaker ◽  
Jennifer Major ◽  
Hanxu Lu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Survival Data ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Cancer Tissue ◽  
Volume Data ◽  
Prostate Cancer Cells

ABSTRACTHigh density lipoprotein (HDL) metabolism, in part, is facilitated by scavenger receptor class B, type 1 (SR-B1) that mediates its uptake into cells. SR-B1 is upregulated in prostate cancer tissue. Here, we report that knockout (KO) of SR-B1 via CRISPR/Cas9 editing led to reduced HDL uptake into prostate cancer cells, and reduced their proliferation in response to HDL. In vivo studies using syngeneic SR-B1 wildtype (SR-B1+/+) and SR-B1 KO (SR-B1−/−) prostate cancer cells in WT and apolipoprotein-AI KO (apoA1-KO) C57BL/6J mice showed that WT hosts, containing higher levels of total and HDL-cholesterol, grew larger tumors than apoA1-KO hosts with lower levels of total and HDL-cholesterol. Furthermore, SR-B1−/− prostate cancer cells formed smaller tumors in WT hosts, than SR-B1+/+ cells in same host model. Tumor volume data was overall similar to survival data. We conclude that tumoral SR-B1 KO reduced HDL-mediated increases in prostate cancer cell proliferation and disease progression.

Abstract 407: High Density Lipoprotein Mediated Protection of Macrophages Against Apoptosis Requires Scavenger Receptor Class B Type 1 Activity and Sphingosine-1-Phosphate

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Kevin Chathely ◽  
Leticia González ◽  
Bernardo Trigatti
Keyword(s):  
High Density Lipoprotein ◽  
Fluorescent Microscopy ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
High Density ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Scavenger Receptor Class ◽  
Class B ◽  
Sphingosine 1 Phosphate

Background/Objectives: Prevention of macrophage apoptosis in advanced atherosclerotic lesions can help stop atherosclerosis progression to vulnerable plaques. High density lipoprotein (HDL) can protect macrophages from apoptosis that has been induced by a variety of agents. We hypothesize that this is the consequence of the sphingolipid, sphingosine-1-phosphate (S1P), specifically carried by HDL, and transferred to S1P receptor 1 (S1PR1) on the cells via the HDL receptor, scavenger receptor class B type 1 (SR-B1). Methods: Apoptosis was induced in murine peritoneal macrophages from wild type and different knockout mice with the ER stress inducing agent tunicamycin. Apoptosis was then observed and detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling through fluorescent microscopy. All experiments were conducted with an n of 3 or 4. Results: Treatment of cells with HDL protected them against tunicamycin induced apoptosis. In contrast, pre-treatment of HDL with S1P lyase, which irreversibly cleaves S1P, eliminated the ability of HDL to protect macrophages. Furthermore, HDL-dependent protection of macrophages against apoptosis required both the HDL receptor SRB1 and the S1PR1. Inhibitor of SRB1’s lipid transport activity also prevented HDL dependant protection against apoptosis. Conclusions: These results suggest that the HDL mediated protection of macrophages against apoptosis may involve SRB1 mediated delivery of S1P from HDL to the S1PR1. Understanding the mechanisms by which HDL elicits atheroprotective signalling in macrophages will provide insight into new targets for therapeutic intervention.

scholarly journals HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner

2018 ◽  
Vol 314 (1) ◽  
pp. H31-H44 ◽  
Author(s):  
Kristina K. Durham ◽  
Kevin M. Chathely ◽  
Kei Cheng Mak ◽  
Abdul Momen ◽  
Cyrus T. Thomas ◽  
...  
Keyword(s):  
Side Effects ◽  
High Density Lipoprotein ◽  
Cardiac Dysfunction ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Scavenger Receptor Class ◽  
Class B ◽  
Induced Apoptosis

Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1Tg/Tg) and wild-type mice (apoA1+/+) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1+/+mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1Tg/Tgmice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1/2 activation in cardiomyocytes.NEW & NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.

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