Enhanced anti-tumor activity of the Multi-Leu peptide PACE4 inhibitor transformed into an albumin-bound tumor-targeting prodrug

Kwiatkowska, Anna; Couture, Frédéric; Aı̈t-Mohand, Samia; Desjardins, Roxane; Dory, Yves L.; Guérin, Brigitte; Day, Robert

doi:10.1038/s41598-018-37568-6

Cited by 11 publications

(13 citation statements)

References 44 publications

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“…The protease encoded by PCSK6 is expressed in many tissues, including the liver, intestine, and brain [ 18 ]. The PCSK6 gene is believed to affect the production of inflammatory factors and to play a role in tumor progression [ 19 ]. However, no study has yet analyzed the role of PCSK6 in ALI, and the relationship between AKAP12 and PCSK6 remains unclear.…”

Section: Introductionmentioning

confidence: 99%

AKAP12 ameliorates liver injury via targeting PI3K/AKT/PCSK6 pathway

Wang

et al. 2022

Redox Biology

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Section: Introductionmentioning

confidence: 99%

AKAP12 ameliorates liver injury via targeting PI3K/AKT/PCSK6 pathway

Wang

et al. 2022

Redox Biology

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“…44 Accordingly, PCSK6 has been proposed as an anti-tumor therapeutic target 45,46 and a bioavailable formulation of an anti-PCSK6 molecule is currently under investigation. 47 In vitro PCSK6 inhibition has already been shown to reduce fibroblast proliferation, migration and invasion in rheumatoid arthritis-associated synovitis, 48 suggesting it as a candidate target for the treatment of pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

Oldham

Lorenzo-Salazar

Molyneaux

et al. 2022

Preprint

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RationaleIdiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. Novel therapies and prognostic biomarkers are needed.ObjectiveTo identify and validate molecular determinants of IPF survival.MethodsA staged genome-wide association study (GWAS) was performed using paired genomic and survival data. Stage I cases were drawn from centers across the US and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplant-free survival (TFS). Stage I variants with nominal significance (p<5×10−5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (p<5×10−8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance.Main ResultsAfter quality controls, 1481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of proprotein convertase subtilisin/kexin type 6 (PCSK6) reaching genome-wide significance (HR 4.11; 95%CI 2.54-6.67; p=9.45×10−9). PCSK6 protein was highly expressed in IPF lung parenchyma and negatively correlated with survival. Peripheral blood PCSK6 gene expression and plasma concentration were associated with reduced transplant-free survival.ConclusionsWe identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein may serve as prognostic biomarker in IPF and potential therapeutic target.

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“…PCa pathology can be heterogeneous from one patient to another, and it is therefore difficult to work with a single cell model that mimics the entire spectrum of PCa 4 . The work performed so far demonstrated efficacy using either peptide inhibitor or gene repression in LNCaP and DU145 cell models 7 , 11 , 16 , 23 , 24 , but these models both have disadvantages for in vivo work. Still, LNCaP had been the central model used to screen compounds and establish key evidence.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of PACE4 pharmacotherapy in JHU-LNCaP-SM preclinical model of androgen independent prostate cancer

Mekdad

Tran

Desjardins

et al. 2022

Sci Rep

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Prostate cancer (PCa) is a complex disease progressing from in situ to invasive or metastatic tumors while also being capable of modulating its androgen dependence. Understanding how novel therapies are working across the different stages of the disease is critical for their proper positioning in the spectrum of PCa treatments. The targeting of proprotein convertase PACE4 (Paired basic Amino Acid-Cleaving Enzyme 4) has been proposed as a novel approach to treat PCa. Animal studies performed on LNCaP xenografts, an androgen-dependent model, already yielded positive results. In this study, we tested PACE4 inhibition on JHU-LNCaP-SM, a newly described androgen-independent model, in cell-based and xenograft assays. Like LNCaP, JHU-LNCaP-SM cells express PACE4 and its oncogenic isoform PACE4-altCT. Using isoform-specific siRNAs, downregulation of PACE4-altCT resulted in JHU-LNCaP-SM growth inhibition. Furthermore, JHU-LNCaP-SM responded to the PACE4 pharmacological inhibitor known as C23 in cell-based assays as well as in athymic nude mice xenografts. These data support the efficacy of PACE4 inhibitors against androgen independent PCa thereby demonstrating that PACE4 is a key target in PCa. The JHU-LNCaP-SM cell line represents a model featuring important aspects of androgen-independent PCa, but it also represents a very convenient model as opposed to LNCaP cells for in vivo studies, as it allows rapid screening due to its high implantation rate and growth characteristics as xenografts.

show abstract

Enhanced anti-tumor activity of the Multi-Leu peptide PACE4 inhibitor transformed into an albumin-bound tumor-targeting prodrug

Cited by 11 publications

References 44 publications

AKAP12 ameliorates liver injury via targeting PI3K/AKT/PCSK6 pathway

AKAP12 ameliorates liver injury via targeting PI3K/AKT/PCSK6 pathway

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

Efficacy of PACE4 pharmacotherapy in JHU-LNCaP-SM preclinical model of androgen independent prostate cancer

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