PCSK9 and cancer: Rethinking the link

Mahboobnia, Khadijeh; Pirro, Matteo; Marini, Ettore; Grignani, Francesco; Bezsonov, Evgeny E.; Jamialahmadi, Tannaz; Sahebkar, Amirhossein

doi:10.1016/j.biopha.2021.111758

Cited by 61 publications

(47 citation statements)

References 267 publications

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“…These findings coincided with high LDL-R mRNA and protein levels in HCC tissues compared to adjacent nontumor tissues [20]. This might indicate that PCSK9 downregulation in HCC would allow increased LDL-R expression and LDL uptake, features also observed in other tumors and associated with malignant progression [171][172][173]. On the other hand, PCSK9 protein levels in the tumors were not linked to tumor grade [20] and in another case report, PCSK9 mRNA levels were even 4-fold higher in the tumor than in the adjacent tissues [164].…”

Section: Pcsk9 and Hcc Progressionsupporting

confidence: 65%

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

Grewal

Buechler

2022

IJMS

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Chronic liver diseases are commonly associated with dysregulated cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease of the proprotein convertase family that is mainly synthetized and secreted by the liver, and represents one of the key regulators of circulating low-density lipoprotein (LDL) cholesterol levels. Its ability to bind and induce LDL-receptor degradation, in particular in the liver, increases circulating LDL-cholesterol levels in the blood. Hence, inhibition of PCSK9 has become a very potent tool for the treatment of hypercholesterolemia. Besides PCSK9 limiting entry of LDL-derived cholesterol, affecting multiple cholesterol-related functions in cells, more recent studies have associated PCSK9 with various other cellular processes, including inflammation, fatty acid metabolism, cancerogenesis and visceral adiposity. It is increasingly becoming evident that additional roles for PCSK9 beyond cholesterol homeostasis are crucial for liver physiology in health and disease, often contributing to pathophysiology. This review will summarize studies analyzing circulating and hepatic PCSK9 levels in patients with chronic liver diseases. The factors affecting PCSK9 levels in the circulation and in hepatocytes, clinically relevant studies and the pathophysiological role of PCSK9 in chronic liver injury are discussed.

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Section: Pcsk9 and Hcc Progressionsupporting

confidence: 65%

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

Grewal

Buechler

2022

IJMS

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“…Khaldoun et al were the first to report the attenuation of cancer cell progression and tumor recurrence in breast cancer via targeting the PCSK9–LDL receptor axis [ 62 ]. In vitro studies demonstrated that pseurotin A (PS) downregulated PCSK9 expression in a dosage-dependent manner and caused a concomitant elevation in LDLR in breast cancer malignancy [ 63 ]. Secondly, endothelial lipase, which is a crucial enzyme for regulating lipoprotein metabolism, intracellular lipid composition, and cytokine expression, is thought to play an important role in cancer cell metabolism via supplying fatty acids to the tumor cells that are required for the tumor cell progression [ 64 ].…”

Section: Future Possibilities Of Targeting Lipid Metabolism To Reduce...mentioning

confidence: 99%

Role of Lipoproteins in the Pathophysiology of Breast Cancer

et al. 2022

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Breast cancer is one of the most common malignancies in women and the leading cause of cancer mortality. Hypercholesterolemia and obesity are potential risk factors for the incidence of breast cancer, and their detection can enhance cancer prevention. In this paper, we discuss the current state of investigations on the importance of lipoproteins, such as low denisity lipoproteins (LDL) and high density lipoproteins (HDL), and cholesterol transporters in the progression of breast cancer, and the therapeutic strategies to reduce breast cancer mortality. Although some research has been unsuccessful at uncovering links between the roles of lipoproteins and breast cancer risk, major scientific trials have found a straight link between LDL levels and incidence of breast cancer, and an inverse link was found between HDL and breast cancer development. Cholesterol and its transporters were shown to have significant importance in the development of breast cancer in studies on breast cancer cell lines and experimental mice models. Instead of cholesterol, 27-hydroxycholesterol, which is a cholesterol metabolite, is thought to promote propagation and metastasis of estrogen receptor-positive breast cancer cell lines. Alteration of lipoproteins via oxidation and HDL glycation are thought to activate many pathways associated with inflammation, thereby promoting cellular proliferation and migration, leading to metastasis while suppressing apoptosis. Medications that lower cholesterol levels and apolipoprotein A-I mimics have appeared to be possible therapeutic agents for preventing excessive cholesterol’s role in promoting the development of breast cancer.

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“…PCSK9 plays a key role in cholesterol metabolism by limiting the number of LDLR [ 179 ]. Additionally, overexpression of PCSK9 downregulates genes responsible for apoptosis and the immune system response [ 180 , 181 ].…”

Section: Pcsk9 and Cancermentioning

confidence: 99%

Insight into the Evolving Role of PCSK9

et al. 2022

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use.

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PCSK9 and cancer: Rethinking the link

Cited by 61 publications

References 267 publications

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

Role of Lipoproteins in the Pathophysiology of Breast Cancer

Insight into the Evolving Role of PCSK9

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