Targeting PCSK9: a promising adjuvant strategy in cancer immunotherapy

Almeida, Catarina R.; Ferreira, Beatriz Henriques; Duarte, Iola F.

doi:10.1038/s41392-021-00530-6

Cited by 27 publications

(17 citation statements)

References 5 publications

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“…Interestingly, PCSK9 mAbs that raise LDLR levels in the liver and other tissues but reduce circulating LDLc were not associated with a significant change in cancer incidence, at least in the short term ( 162 , 187 ). However, upon PCSK9 neutralization, extremely low circulating LDLc levels (originating from liver VLDL) will not result in excessive internalization by supernumerary LDLR ( 98 ), and may rather reduce tumor growth ( 267 , 268 ). Indeed, it was reported that PCSK9 deficiency reduces melanoma metastasis in mouse liver ( 269 ) and that LOF and GOF variants are associated with lower and higher incidence of human breast cancer, respectively ( 270 ).…”

Section: Pcsk9 and Cancer/metastasismentioning

confidence: 99%

The Multifaceted Biology of PCSK9

2021

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This article reviews the discovery of PCSK9, its structure-function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating LDL-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain (CHRD), its binding to the secreted cytosolic cyclase associated protein 1 (CAP-1), and possibly another membrane-bound “protein X”. Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the anti-tumoral activity of CD8 + T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors (PCSK9i) that reduces by 50-60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 mAb or siRNA could be added to current immunotherapies in cancer/metastasis.

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Section: Pcsk9 and Cancer/metastasismentioning

confidence: 99%

The Multifaceted Biology of PCSK9

2021

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“…Inhibition of PCSK9 protects LDLR, the latter are recycled at the surface of the hepatocytes each time they internalize LDL cholesterol, resulting in lower circulating levels of LDL-C. Although PCSK9 and its inhibition have been principally studied in atherosclerosis and cardiovascular disease [ 17 – 20 ], a growing number of reports suggest a role of PCSK9 in cancers [ 26 – 30 ], not only as a cholesterol supplier, but also as an immune response down-regulator, by triggering degradation of the Major Histocompatibility Complex 1 (MHC-I) receptor [ 31 – 33 ]. Inhibition of PCSK9 not only protects LDLR but also MHC-I from PCSK9-induced degradation [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Circulating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancers

et al. 2022

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Background / synopsis Cholesterol and lipids play an important role in sustaining tumor growth and metastasis in a large variety of cancers. ANGPTL3 and PCSK9 modify circulating cholesterol levels, thus availability of lipids to peripheral cells. Little is known on the role, if any, of circulating lipid-related factors such as PCSK9, ANGPTL3 and lipoprotein (a) in cancers. Objective/purpose To compare circulating levels of PCSK9, ANGPTL3, and Lp(a) in women with stage III breast cancer versus women with premalignant or benign breast lesions. Methods Twenty-three plasma samples from women diagnosed with a stage III breast cancer (ductal, lobular or mixed) were matched for age with twenty-three plasma samples from women bearing premalignant (stage 0, n = 9) or benign (n = 14) breast lesions. The lipid profile (Apo B, total cholesterol, HDL cholesterol and triglycerides levels) and Lp(a) were measured on a Roche Modular analytical platform, whereas LDL levels were calculated with the Friedewald formula. ANGPTL3 and PCSK9 plasma levels were quantitated by ELISA. All statistical analyses were performed using SAS software version 9.4. Results PCSK9 levels were significantly higher in women with stage III breast cancer compared to age-matched counterparts presenting a benign lesion (95.9 ± 27.1 ng/mL vs. 78.5 ± 19.3 ng/mL, p < 0.05, n = 14). Moreover, PCSK9 levels positively correlated with breast disease severity (benign, stage 0, stage III) (Rho = 0.34, p < 0.05, n = 46). In contrast, ANGPTL3 and Lp(a) plasma levels did not display any association with breast disease status and lipids did not correlate with disease severity. Conclusion In this small cohort of 46 women, PCSK9 levels tended to increase with the severity of the breast disease. Given that PCSK9 plays an important role in maintaining cholesterolemia, and a potential role in tumor evasion, present results warrant further investigation into a possible association between PCSK9 levels and breast cancer severity in larger cohorts of women.

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“…Although one mechanistic hypothesis for the link between PCSK9 and cancer progression is the modulation of cholesterol supply to the tumor ( Huang et al., 2016 ), a recent article described PCSK9 as a regulator of the major histocompatibility protein class I (MHCI) recycling by promoting its relocation and degradation in the lysosome ( Liu et al., 2020 ). This result identified PCSK9 as a promising strategy in cancer immunotherapy ( Almeida et al., 2021 ). Our data suggest that PCSK9 may directly regulate cell proliferation, potentially through a modulation of NODAL signaling.…”

Section: Discussionmentioning

confidence: 94%

PCSK9 regulates the NODAL signaling pathway and cellular proliferation in hiPSCs

et al. 2021

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Summary Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) cholesterol metabolism and the target of lipid-lowering drugs. PCSK9 is mainly expressed in hepatocytes. Here, we show that PCSK9 is highly expressed in undifferentiated human induced pluripotent stem cells (hiPSCs). PCSK9 inhibition in hiPSCs with the use of short hairpin RNA (shRNA), CRISPR/cas9-mediated knockout, or endogenous PCSK9 loss-of-function mutation R104C/V114A unveiled its new role as a potential cell cycle regulator through the NODAL signaling pathway. In fact, PCSK9 inhibition leads to a decrease of SMAD2 phosphorylation and hiPSCs proliferation. Conversely, PCSK9 overexpression stimulates hiPSCs proliferation. PCSK9 can interfere with the NODAL pathway by regulating the expression of its endogenous inhibitor DACT2, which is involved in transforming growth factor (TGF) β-R1 lysosomal degradation. Using different PCSK9 constructs, we show that PCSK9 interacts with DACT2 through its Cys-His-rich domain (CHRD) domain. Altogether these data highlight a new role of PCSK9 in cellular proliferation and development.

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Targeting PCSK9: a promising adjuvant strategy in cancer immunotherapy

Cited by 27 publications

References 5 publications

The Multifaceted Biology of PCSK9

The Multifaceted Biology of PCSK9

Circulating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancers

PCSK9 regulates the NODAL signaling pathway and cellular proliferation in hiPSCs

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