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Antitumor activity and molecular mechanism of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition

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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proprotein convertase family of proteins that activate other proteins in cells. Functionally, PCSK9 binds to the receptor of low-density lipoprotein particles (LDL) to regulate cholesterol metabolism and lipoprotein homeostasis in human body. PCSK9 inhibition is a novel pharmacological strategy to control hypercholesterolemia and cardiovascular diseases. Recently accumulating evidence realizes that PCSK9 possesses other roles in cells, such as regulation of tissue inflammatory response, intratumoral immune cell infiltration, and tumor progression. This review discussed the advancement of PCSK9 research on its role and underlying mechanisms in tumor development and progression. For example, PCSK9 inhibition could attenuate progression of breast cancer, glioma, colon tumor, hepatocellular cancer, prostate cancer, and lung adenocarcinoma and promote apoptosis of glioma, prostate cancer, and hepatocellular cancer cells. PCSK9 deficiency could reduce liver metastasis of B16F1 melanoma cells by lowering the circulating cholesterol levels. PCSK9 gene knockdown substantially attenuated mouse tumor growth in vivo by activation of cytotoxic T cells, although PCSK9 knockdown had no effect on morphology and growth rate of different mouse cancer cell lines in vitro. PCSK9 inhibition thus can be used to control human cancers. Future preclinical and clinical studies are warranted to define anti-tumor activity of PCSK9 inhibition.

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Abbreviations

PCSK9:

Proprotein convertase subtilisin/kexin type 9

LDL:

Low-density lipoprotein particles

LDL:

Cholesterol low-density lipoprotein

LDLR:

LDL receptor

VLDL:

Very low-density lipoprotein

TNF-α:

Tumor necrosis factor-α

IL:

Interleukin

MCP-1:

Monocyte chemoattractant protein-1

MIP-2:

Macrophage inflammatory protein 2

SREBPs:

Sterol regulatory element-binding proteins

HNF1:

Hepatocyte nuclear factor 1

mTORC1:

Mammalian target of rapamycin complex 1

HCC:

Hepatic cell carcinoma

ApoER2:

Apolipoprotein E receptor-2

NMDA:

N-methyl-D-aspartic acid

MBTPS1:

Membrane-Bound Transcription Factor Peptidase, Site 1

TCGA:

The Cancer Genome Atlas

SOAT1:

Sterol O-acyltransferase 1

SQLE:

Squalene monooxygenase

ABCA1:

ATP-binding cassette, sub-family A, member 1

SCARB1:

Scavenger receptor class B member 1

Apo AI:

Apolipoprotein AI

Apo B:

Apolipoprotein B

THW:

Thyroid hormone withdrawal

ABI:

Ankle brachial inde

sLOX-1:

Soluble lectin-like oxidized LDL receptor 1

TSH:

Thyroid-stimulating hormone

NENs:

Neuroendocrine neoplasms

XIAP:

X-chromosome-linked inhibitor of apoptosis

cyt-C:

Cytochrome C

ERS:

Endoplasmic reticulum stress

GRP78:

Glucose-regulated protein 78 kDa

PERK:

Protein kinase R-like ER kinase

eIF:

Eukaryotic initiation factor

HCD:

High cholesterol diet

TC:

Total cholesterol

IBD:

Inflammatory bowel disease

TNBS:

Trinitrobenzene sulfonic acid

MPO:

Myeloperoxidase

IL-1β:

Interleukin-1β

TLR4:

Toll-like receptor 4

NF-κB:

Nuclear factor-kappa B

MHC I:

Major histocompatibility protein class I

mAb:

Monoclonal antibodies

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Funding

This work was supported by the National Natural Science Foundation of China [grant number 81803570]; the Postdoctoral Science Foundation of China [grant number 2019M652411]; the Postdoctoral Innovation Project of Shandong Province [grant number 201902044]; and the Jinan Science and Technology Bureau [grant number 201907111].

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  1. Department of Pharmacy, Jinan Central Hospital Affiliated to Shandong First Medical University, Shandong, Jinan, China

    Huimin Sun, Wen Meng, Jie Zhu & Lu Wang

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  1. Huimin Sun
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  2. Wen Meng
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The authors declare that all data were generated in-house and that no paper mill was used. Huimin Sun: Resources, Writing — original draft; Wen Meng: Writing — original draft; Jie Zhu: Review and editing, Supervision; Lu Wang: Ideas, Conceptualization, Supervision.

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Sun, H., Meng, W., Zhu, J. et al. Antitumor activity and molecular mechanism of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. Naunyn-Schmiedeberg's Arch Pharmacol 395, 643–658 (2022). https://doi.org/10.1007/s00210-022-02200-y

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