Internalization by Multiple Endocytic Pathways and Lysosomal Processing Impact Maspin-Based Therapeutics

Bodenstine, Thomas M.; Seftor, Richard E.B.; Seftor, Elisabeth A.; Khalkhali‐Ellis, Zhila; Samii, Nicole A.; Monarrez, J. Cesar; Chandler, G. Scott; Pemberton, Philip A.; Hendrix, Mary J.C.

doi:10.1158/1541-7786.mcr-14-0067

Cited by 18 publications

(17 citation statements)

References 46 publications

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“…The short time required for their influence to be seen indicates a dynamic regulation of cellular processes, similar to prior observations with full length maspin [6]. The peptides could either have been taken up into cells as recently demonstrated for full length maspin [33] or acting through cell surface receptors as discussed. Either of these mechanisms could account for the effects on downstream signalling processes demonstrated.…”

Section: Discussionsupporting

confidence: 80%

Identification of novel peptide motifs in the serpin maspin that affect vascular smooth muscle cell function

Jenkinson¹,

Brown²,

Ombor³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Identification of novel peptide motifs in the serpin maspin that affect vascular smooth muscle cell function, BBAMolecular Cell Research (2016Research ( ), doi:10.1016Research ( /j.bbamcr.2016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 2 AbstractMaspin is a non-inhibitory member of the serpin family that affects cell behaviours related to migration and survival. We have previously shown that peptides of the isolated G α-helix (G-helix) domain of maspin show bioactivity. Migration, invasion, adhesion and proliferation of vascular smooth muscle cells (VSMC) are important processes that contribute to the build-up of atherosclerotic plaques. Here we report the use of functional assays of these behaviours to investigate whether other maspin-derived peptides impact directly on VSMC; focusing on potential anti-atherogenic properties. We designed 18 new peptides from the structural moieties of maspin above ten amino acid residues in length and considered them beside the existing G-helix peptides. Of the novel peptides screened those with the sequences of maspin strand 4 and 5 of beta sheet B (S4B and S5B) reduced VSMC migration, invasion and proliferation, as well as increasing cell adhesion. A longer peptide combining these consecutive sequences showed a potentiation of responses, and a 7-mer contained all essential elements for functionality. This is the first time that these parts of maspin have been highlighted as having key roles affecting cell function. We present evidence for a mechanism whereby S4B and S5B act through ERK1/2 and AMP-activated protein kinase (AMPK) to influence VSMC responses. Graphic AbstractSchematic depiction of the effect of maspin peptides on VSMC behaviours

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Section: Discussionsupporting

confidence: 80%

Identification of novel peptide motifs in the serpin maspin that affect vascular smooth muscle cell function

Jenkinson¹,

Brown²,

Ombor³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Re-expression of Maspin or treatment with rMaspin decreases tumor growth and metastasis using in vivo experiments (Zou et al, 1994;Bodenstine et al, 2012;Berardi et al, 2013). Recently, a paper by Bodenstine et al, (2014) considered recombinant Maspin (rMaspin), which alters invasive properties when directly applied to cancer cells. This study indicates that cellular processing of rMaspin plays a key role by affecting its biologic activity and highlights the need for new approaches aimed at increasing the availability of rMaspin when used to treat cancer.…”

Section: Resultsmentioning

confidence: 99%

An in silico model to demonstrate the effects of Maspin on cancer cell dynamics

Al-Mamun

Farid

Ravenhil

et al. 2016

Journal of Theoretical Biology

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Most cancer treatments efficacy depends on tumor metastasis suppression, where tumor suppressor genes play an important role. Maspin (Mammary Serine Protease Inhibitor), an non-inhibitory serpin has been reported as a potential tumor suppressor to influence cell migration, adhesion, proliferation and apoptosis in in vitro and in vivo experiments in last two decades. Lack of computational investigations hinders its ability to go through clinical trials. Previously, we reported first computational model for maspin effects on tumor growth using artificial neural network and cellular automata paradigm with in vitro data support.This paper extends the previous in silico model by encompassing how maspin influences cell migration and the cell-extracellular matrix interaction in subcellular level. A feedforward neural network was used to define each cell behavior (proliferation, quiescence, apoptosis) which followed a cell-cycle algorithm to show the microenvironment impacts over tumor growth. Furthermore, the model concentrates how the in silico experiments results can further confirm the fact that maspin reduces cell migration using specific in vitro data verification method. The data collected from in vitro and in silico experiments formulates an unsupervised learning problem which can be solved by using different clustering algorithms. A density based clustering technique was developed to measure the similarity between two datasets based on the number of links between instances. Our proposed clustering algorithm first finds the nearest neighbors of each instance, and then redefines the similarity between pairs of instances in terms of how many nearest neighbors share the two instances. The number of links between two instances is defined as the number of common neighbors they have. The results showed significant resemblances with in vitro experimental data. The results also offer a new insight into the dynamics of maspin and establish as a metastasis suppressor gene for further molecular research.

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“…Low-dose maspin plus paclitaxel resulted in 41% tumor growth inhibition which was superior to maspin or paclitaxel alone (79). The r-maspin was found in cytoplasmic vesicles through multiple endocytic mechanisms of uptake (80,81). In addition to the general shortcomings of many therapeutic proteins, presently, systematic optimization of the anti-metastatic function of r-maspin is hampered by insufficient knowledge of the functional contribution of membrane-associated, cytoplasmic and nuclear maspin.…”

Section: Target Validation Experiments In Breast-and Prostate Cancerrmentioning

confidence: 99%

Potential of Protein-based Anti-metastatic Therapy with Serpins and Inter α-Trypsin Inhibitors

Weidle

Birzele

Tiefenthaler

2018

Cancer Genomics Proteomics

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In this review we summarize the principles of anti-metastatic therapy with selected serpin family proteins, such as pigment epithelial-derived factor (PEDF) and maspin, as well as inter α-trypsin inhibitor (IαIs) light chains (bikunin) and heavy chains (ITIHs). Case-by-case, antimetastatic activity may be dependent or independent of the protease-inhibitory activity of the corresponding proteins. We discuss the incidence of target deregulation in different tumor entities, mechanisms of deregulation, context-dependent functional issues as well as in vitro and in vivo target validation studies with transfected tumor cells or recombinant protein as anti-metastatic agents. Finally, we comment on possible clinical evaluation of these proteins in adjuvant therapy.

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Internalization by Multiple Endocytic Pathways and Lysosomal Processing Impact Maspin-Based Therapeutics

Cited by 18 publications

References 46 publications

Identification of novel peptide motifs in the serpin maspin that affect vascular smooth muscle cell function

Identification of novel peptide motifs in the serpin maspin that affect vascular smooth muscle cell function

An in silico model to demonstrate the effects of Maspin on cancer cell dynamics

Potential of Protein-based Anti-metastatic Therapy with Serpins and Inter α-Trypsin Inhibitors

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