Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer

Liu, Xinjian; Bao, Xiaoyong; Hu, Mengjie; Chang, Hanman; Jiao, Meng; Cheng, Jin; Xie, Liyi; Huang, Qian; Li, Fang; Li, Chuan-Yuan

doi:10.1038/s41586-020-2911-7

Cited by 278 publications

(332 citation statements)

References 43 publications

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“…4 ). However, it remains to be investigated whether this polyanionic compound is able to protect small animals such as hACE2-expressing mice or Syrian hamsters from SARS-CoV-2 infection by blocking the viral S protein-associated entry step 38 , 39 . In addition, because CGNs have intrinsic anti-coagulant activity, any unwarranted side effects should be reviewed before clinical application.…”

Section: Discussionmentioning

confidence: 99%

Antiviral activity of lambda-carrageenan against influenza viruses and severe acute respiratory syndrome coronavirus 2

Jang

Shin

Lee

et al. 2021

Sci Rep

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Influenza virus and coronavirus, belonging to enveloped RNA viruses, are major causes of human respiratory diseases. The aim of this study was to investigate the broad spectrum antiviral activity of a naturally existing sulfated polysaccharide, lambda-carrageenan (λ-CGN), purified from marine red algae. Cell culture-based assays revealed that the macromolecule efficiently inhibited both influenza A and B viruses with EC50 values ranging from 0.3 to 1.4 μg/ml, as well as currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with an EC50 value of 0.9 ± 1.1 μg/ml. No toxicity to the host cells was observed at concentrations up to 300 μg/ml. Plaque titration and western blot analysis verified that λ-CGN reduced expression of viral proteins in cell lysates and suppressed progeny virus production in culture supernatants in a dose-dependent manner. This polyanionic compound exerts antiviral activity by targeting viral attachment to cell surface receptors and preventing virus entry. Moreover, its intranasal administration to mice during influenza A viral challenge not only alleviated infection-mediated reductions in body weight but also protected 60% of mice from virus-induced mortality. Thus, λ-CGN could be a promising antiviral agent for preventing infection with several respiratory viruses.

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Section: Discussionmentioning

confidence: 99%

Antiviral activity of lambda-carrageenan against influenza viruses and severe acute respiratory syndrome coronavirus 2

Jang

Shin

Lee

et al. 2021

Sci Rep

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show abstract

“…As a critical regulatory molecule in the lipid transport process, PCSK9 interferes with the utilization of LDL and triglycerides by degrading LDLR [ 2 , 3 ]. In addition to regulating lipid transport, PCSK9 has many other effects on cell functions, such as in the processes of viral infection [ 29 – 31 ], insulin resistance [ 8 , 32 ], development of the central nervous system [ 5 ], tumor apoptosis [ 9 , 10 ] and tumor immunity [ 33 , 34 ]. Therefore, we hypothesized that PCSK9 might play a role in the progression of HCC.…”

Section: Discussionmentioning

confidence: 99%

PCSK9 promotes tumor growth by inhibiting tumor cell apoptosis in hepatocellular carcinoma

et al. 2021

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Background Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key enzymes in the process of lipid transport, is involved in the disease progression of various types of tumors. This article is to study the role of PCSK9 in the progression of hepatocellular carcinoma (HCC). Methods Immunohistochemistry was used to assess the expression of PCSK9 in tumor specimens from 105 HCC patients who underwent curative resection. Western blotting and quantitative real-time PCR were used to test the protein and mRNA expression levels in HCC cell lines. Cell Counting Kit-8 (CCK-8) and clone formation assays were performed to evaluate the proliferation ability of different kinds of cells in vitro. Flow cytometry was used to analyze cell cycle distribution and apoptosis rate. A xenograft model was established to study the effect of PCSK9 on HCC growth in vivo. TUNEL and immunofluorescence assays were used to detect cell apoptosis. Results High expression of PCSK9 in tumor tissues was related to microvascular invasion (p = 0.036) and large tumor size (p = 0.001) in HCC patients. Overall survival and disease-free survival after surgery were poor in patients with high expression of PCSK9 (p = 0.035 and p = 0.007, respectively). In vivo and in vitro experiments showed that PCSK9 promoted the growth of HCC by inhibiting cell apoptosis. A mechanistic study revealed that PCSK9 increases FASN expression, thereby inhibiting apoptosis of HCC cells via the Bax/Bcl-2/Caspase9/Caspase3 pathway. Conclusions PCSK9 expression level in HCC is an indicator of poor prognosis for patients with HCC. FASN-mediated anti-apoptosis plays an important role in PCSK9-induced HCC progression.

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“…Interestingly, it has been shown in mice that SARS-CoV-1 (the coronavirus that caused the SARS epidemic in 2003) infection downregulates ACE2 protein (but not ACE) contributing to severe lung injury [ 23 ]. The ACE2-dependent pathogenicity of SARS-CoV-2 has been also confirmed in mice expressing human ACE2 [ 24 ]. Suppressed ACE2 expression and locally increased ANGII production can induce leakage of pulmonary blood vessels (a hallmark in ARDS pathogenesis) via AT1R stimulation [ 25 ].…”

Section: The Critically Balanced Ace/angii/at1r and Ace2/ang(1–7)/masmentioning

confidence: 99%

Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications

et al. 2021

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Background Gaining further insights into SARS-CoV-2 routes of infection and the underlying pathobiology of COVID-19 will support the design of rational treatments targeting the life cycle of the virus and/or the adverse effects (e.g., multi-organ collapse) that are triggered by COVID-19-mediated adult respiratory distress syndrome (ARDS) and/or other pathologies. Main body COVID-19 is a two-phase disease being marked by (phase 1) increased virus transmission and infection rates due to the wide expression of the main infection-related ACE2, TMPRSS2 and CTSB/L human genes in tissues of the respiratory and gastrointestinal tract, as well as by (phase 2) host- and probably sex- and/or age-specific uncontrolled inflammatory immune responses which drive hyper-cytokinemia, aggressive inflammation and (due to broad organotropism of SARS-CoV-2) collateral tissue damage and systemic failure likely because of imbalanced ACE/ANGII/AT1R and ACE2/ANG(1–7)/MASR axes signaling. Conclusion Here we discuss SARS-CoV-2 life cycle and a number of approaches aiming to suppress viral infection rates or propagation; increase virus antigen presentation in order to activate a robust and durable adaptive immune response from the host, and/or mitigate the ARDS-related “cytokine storm” and collateral tissue damage that triggers the severe life-threatening complications of COVID-19.

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Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer

Cited by 278 publications

References 43 publications

Antiviral activity of lambda-carrageenan against influenza viruses and severe acute respiratory syndrome coronavirus 2

Antiviral activity of lambda-carrageenan against influenza viruses and severe acute respiratory syndrome coronavirus 2

PCSK9 promotes tumor growth by inhibiting tumor cell apoptosis in hepatocellular carcinoma

Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications

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