Loss of Proprotein Convertase Furin in Mammary Gland Impairs proIGF1R and proIR Processing and Suppresses Tumorigenesis in Triple Negative Breast Cancer

He, Zongsheng; Khatib, Abdel‐Majid; Creemers, John W.M.

doi:10.3390/cancers12092686

Cited by 16 publications

(13 citation statements)

References 56 publications

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“…Our results revealed that in pancreatic β cells, proIR is non-redundantly cleaved by FURIN. Similar results were observed in colorectal cell lines and mouse mammary gland tissue lacking Furin [7,8]. In contrast, in liver of FurKO mice, we show a complete redundancy of proIR cleavage, which is in agreement with our previous work in which an inducible promoter was used to inactivate Furin [9].…”

Section: Discussionsupporting

confidence: 92%

“…However, FURIN was put forward as the physiological PC for processing of the proIR in the secretory pathway and PACE4 at the cell surface when FURIN activity is reduced [6]. In colorectal cell lines and in mouse mammary gland tissue, genetic ablation of Furin indeed blocked proIR processing, suggesting non-redundant cleavage by FURIN [7,8]. However, the proIR was normally processed in liver of an inducible Furin knockout mouse model, revealing tissue-specific redundancy [9].…”

Section: Introductionmentioning

confidence: 99%

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Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

Coppola

Brouwers

Meulemans

et al. 2021

IJMS

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The insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic β cells is still controversial. In this study, we investigated the cleavage of the IR by the proprotein convertase FURIN in β cells and hepatocytes, and the contribution of the IR in pancreatic β cells and liver to glucose homeostasis. β-cell-specific Furin knockout (βFurKO) mice were glucose intolerant, but liver-specific Furin knockout (LFurKO) mice were normoglycemic. Processing of the IR was blocked in βFurKO cells, but unaffected in LFurKO mice. Most strikingly, glucose homeostasis in β-cell-specific IR knockout (βIRKO) mice was normal in younger mice (up to 20 weeks), and only mildly affected in older mice (24 weeks). In conclusion, FURIN cleaves the IR non-redundantly in β cells, but redundantly in liver. Furthermore, we demonstrated that the IR in β cells plays a limited role in glucose homeostasis.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

Coppola

Brouwers

Meulemans

et al. 2021

IJMS

Self Cite

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“…This study can be generalized to SARS-CoV-2 induced infection, so it is probable that the effect of this virus on platelet CD147 may have the same results, but further studies are required to prove this claim. Regarding the other SARS-CoV-2 receptor, furin, it has been demonstrated that furin is closely associated with PI3K/AKT signaling activation [ 23 ]. In addition to over-activation of the PI3K/AKT signaling pathway by SARS-CoV-2, the role of this pathway in SARS-CoV-2 entry to the host cells can be examined.…”

Section: Introductionmentioning

confidence: 99%

The probable role and therapeutic potential of the PI3K/AKT signaling pathway in SARS-CoV-2 induced coagulopathy

2022

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Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with a high mortality rate. The majority of deaths in this disease are caused by ARDS (acute respiratory distress syndrome) followed by cytokine storm and coagulation complications. Although alterations in the level of the number of coagulation factors have been detected in samples from COVID-19 patients, the direct molecular mechanism which has been involved in this pathologic process has not been explored yet. The PI3K/AKT signaling pathway is an intracellular pathway which plays a central role in cell survival. Also, in recent years the association between this pathway and coagulopathies has been well clarified. Therefore, based on the evidence on over-activity of the PI3K/AKT signaling pathway in SARS-CoV-2 infection, in the current review, the probable role of this cellular pathway as a therapeutic target for the prevention of coagulation complications in patients with COVID-19 is discussed.

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“…Regulating furin activity disclosed its importance in processing cancer-related substrates and showed that high furin activity promotes tumorigenesis [6,23]. For example, loss of furin in T cells suppresses mammary tumorigenesis of triplenegative breast cancer [24], likely by impairing its substrates proIGF1R and proIR processing [25]. Furin also plays a critical role in KRAS and BRAF-related ERK/MAPK pathway activation and tumorigenesis of colorectal cancer [26].…”

Section: Introductionmentioning

confidence: 99%

COVID-19 disease and malignant cancers: The impact for the furin gene expression in susceptibility to SARS-CoV-2

Li¹,

Liu²,

Zhang³

et al. 2021

Int. J. Biol. Sci.

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Furin is a proprotein convertase that activates different kinds of regulatory proteins, including SARS-CoV-2 spike protein which contains an additional furin-specific cleavage site. It is essential in predicting cancer patients' susceptibility to SARS-CoV-2 and the disease outcomes due to varying furin expressions in tumor tissues. In this study, we analyzed furin's expression, methylation, mutation rate, functional enrichment, survival rate and COVID-19 outcomes in normal and cancer tissues using online databases, and our IHC. As a result, furin presented with biased expression profiles in normal tissues, showing 12.25-fold higher than ACE2 in the lungs. The furin expression in tumors were significantly increased in ESCA and TGCT, and decreased in DLBC and THYM, indicating furin may play critical mechanistic functions in COVID-19 viral entry into cells in these cancer patients. Line with furin over/downexpression, furin promoter hypo-/hyper-methylation may be the regulatory cause of disease and lead to pathogenesis of ESCA and THYM. Furthermore, presence of FURIN−201 isoform with functional domains (P_proprotein, Peptidase_S8 and S8_pro-domain) is highest in all cancer types in comparison to other isoforms, demonstrating its use in tumorigenesis and SARS-Cov-2 entry into tumor tissues. Furin mutation frequency was highest in UCES, and its mutation might elevate ACE2 expression in LUAD and UCEC, reduce ACE2 expression in COAD, elevate HSPA5 expression in PAAD, and elevate TMPRSS2 expression in BRCA. These results showed that furin mutations mostly increased expression of ACE2, HSPA5, and TMPRSS2 in certain cancers, indicating furin mutations might facilitate COVID-19 cell entry in cancer patients. In addition, high expression of furin was significantly inversely correlated with long overall survival (OS) in LGG and correlated with long OS in COAD and KIRC, indicating that it could be used as a favorable prognostic marker for cancer patients' survival. GO and KEGG demonstrated that furin was mostly enriched in genes for metabolic and biosynthetic processes, retinal dehydrogenase activity, tRNA methyltransferase activity, and genes involving COVID-19, further supporting its role in COVID-19 and cancer metabolism. Moreover, Cordycepin (CD) inhibited furin expression in a dosage dependent manner. Altogether, furin's high expression might not only implies increased susceptibility to SARS-CoV-2 and higher severity of COVID-19 symptoms in cancer patients, but also it highlights the need for cancer treatment and therapy during the COVID-19 pandemic. CD might have a potential to develop an anti-SARS-CoV-2 drug through inhibiting furin expression.

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Loss of Proprotein Convertase Furin in Mammary Gland Impairs proIGF1R and proIR Processing and Suppresses Tumorigenesis in Triple Negative Breast Cancer

Cited by 16 publications

References 56 publications

Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

The probable role and therapeutic potential of the PI3K/AKT signaling pathway in SARS-CoV-2 induced coagulopathy

COVID-19 disease and malignant cancers: The impact for the furin gene expression in susceptibility to SARS-CoV-2

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