Determination of cell uptake pathways for tumor inhibitor lysyl oxidase propeptide

Ozdener, Gokhan Baris; Bais, Manish V.; Trackman, Philip C.

doi:10.1016/j.molonc.2015.07.005

Cited by 27 publications

(27 citation statements)

References 120 publications

(162 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On the contrary, PI3K-independent macropinocytosis is linked to Cdc42 activation resulting in filopodia formation. 44,45 In the present study, we found that expression of onco-Dbl markedly induced the formation of stress fiber and thereby increased the quantities of lamellipodia ( Figure 6). These enhanced actin polymerizations and lamellipodia formation occur alongside macropinocytosis promotion but with the inhibition of CME and CvME (Figure 1), indicating that the macropinocytosis of Tat/pDNA is most likely PI3K-dependent and controlled by the Rac1 activation-mediated actin cytoskeleton rearrangement mechanism.…”

Section: Discussionsupporting

confidence: 60%

Macropinocytosis activated by oncogenic Dbl enables specific targeted delivery of Tat/pDNA nano-complexes into ovarian cancer cells

Niu¹,

Gao²,

Qi³

et al. 2018

IJN

View full text Add to dashboard Cite

BackgroundSuccessful implementation of gene therapy heavily relies on efficiently delivering genetic materials and specific targeting into cells. Oncogene-driven endocytosis stimulates nutrient uptake and also develops an endocytosis-mediated defense against therapeutic agents. Cell-penetrating peptides, typically HIV-Tat, are well known for efficient delivery of nucleic acid drugs but lack targeting specificity. Various passive targeting strategies were pursued to enhance the tumor targeting efficiency; however, they are still limited by complicated cellular endocytosis routes and the heterogeneity of cancer types.MethodsTat/pDNA complexes were noncovalently compacted and their physiochemical properties were determined. The siRNA pool and pLV-RNAi-GFP lentivirus were used to knock down dbl oncogene (originally isolated from diffuse B-cell lymphoma) expression, and its overexpression was performed by plasmid transient transfection. The cellular uptake of fluorescent ligands was quantified by confocal imaging and flow cytometry analysis. The transgene efficiency was determined by the Luciferase expression assay. Rho GTPase activation was checked by the GST-Rho GTPase-binding domain pull-down assay.ResultspGL3 plasmid DNA was noncovalently compacted with the Tat peptide into nano-size complexes at high N/P ratios. Macropinocytosis, a clathrin- and caveolin-independent endocytosis process, was shown to contribute to the uptake of middle-sized (∼600 nm) Tat/pGL3 complexes. Cell-type-specific variation in macropinocytosis was essentially controlled by the action of the Dbl oncogene. Onco-Dbl presentation constantly induced a high level of macropinocytosis activity in ovarian cancer cells. Onco-Dbl overexpression hyperstimulated macropinocytosis enhancement in cells mainly through actin cytoskeleton reorganization mediated by the PH domain and Rac1 activation. The Dbl-driven Rho GTPase signaling collectively determined the cell-type-specific macropinocytosis phenotype.ConclusionSuch an aspect can be exploited to selectively confer targeted delivery of Tat/pDNA nano-complexes into ovarian cancer cells. Our work provides a novel alternative for targeted delivery of cell-penetrating peptide-based nucleic acid drugs into certain tumor types if specific endocytosis pathways are used.

show abstract

Section: Discussionsupporting

confidence: 60%

Macropinocytosis activated by oncogenic Dbl enables specific targeted delivery of Tat/pDNA nano-complexes into ovarian cancer cells

Niu¹,

Gao²,

Qi³

et al. 2018

IJN

View full text Add to dashboard Cite

show abstract

“…Therefore, the pathways of LOX-PP cell uptake were investigated in a variety of cell lines to assess for possible avenues to enhance uptake and therefore potentially block cancer cell growth and metastatic potential. Data demonstrated that macropinocytosis is employed by most cell lines, while clathrin-dependent pathways serve as secondary uptake pathways in some cell lines (Ozdener et al 2016). Ongoing work is focusing on modifying the structure of LOX-PP to enhance its uptake by cancer cells and increase its effectiveness, and to establish which targets are the most important in mediating the tumor inhibitor properties of LOX-PP.…”

Section: Lox-pp and Tumor Suppressionmentioning

confidence: 99%

Functional importance of lysyl oxidase family propeptide regions

Trackman

2017

J. Cell Commun. Signal.

Self Cite

View full text Add to dashboard Cite

The lysyl oxidase family of proteins is primarily known for its critical role in catalyzing extracellular oxidative deamination of hydroxylysine and lysine residues in collagens, and lysine residues in elastin required for connective tissue structure and function. Lysyl oxidases have additional important biological functions in health and disease. While the enzyme domains are highly conserved, the propeptide regions are less uniform, and have biological activity, some of which are independent of their respective enzymes. This review summarizes what has been published regarding the functions of the propeptide regions of this family of proteins in the context of extracellular matrix biosynthesis, fibrosis and cancer biology. Although much has been learned, there is a need for greater attention to structure/function relationships and mechanisms to more fully understand these multifunctional proteins.

show abstract

“…The major obstacle to easily capturing and analyzing the CTCs lies in their rarity, as CTCs are quite literally one in a million or billion among other cells in the blood[26]. Another challenge has to do with the heterogeneity of CTCs, as they can vary in surface protein expression, size, and physical characteristics, and often travel through the bloodstream in clusters[14].…”

Section: Liquid Biopsy Biomarkers and Biogenesismentioning

confidence: 99%

Advances in liquid biopsy on-chip for cancer management: Technologies, biomarkers, and clinical analysis

Tadimety

Closson

et al. 2018

Critical Reviews in Clinical Laboratory Sciences

View full text Add to dashboard Cite

Liquid biopsy, as a minimally invasive method of gleaning insight into the dynamics of diseases through a patient fluid sample, has been growing in popularity for cancer diagnosis, prognosis, and monitoring. While many technologies have been developed and validated in research laboratories, there has also been a push to expand these technologies into other clinical settings and as point of-care devices. In this review we discuss and evaluate microchip-based technologies for circulating tumor cell (CTC), exosome, and circulating tumor nucleic acid (ctNA) capture, detection, and analysis. Such integrated systems streamline otherwise multiple-step, manual operations to get a sample-to-answer quantitation. In addition, analysis of disease biomarkers is suited to point of care settings because of ease of use, low consumption of sample and reagents, and high throughput. We also cover the basics of biomarkers and their detection in biological fluid samples suitable for liquid biopsy on-chip. We focus on emerging technologies that process a small patient sample with high spatial-temporal resolution and derive clinically meaningful results through on-chip biomarker sensing and downstream molecular analysis in a simple workflow. This critical review is meant as a resource for those interested in developing technologies for capture, detection, and analysis platforms for liquid biopsy in a variety of settings.

show abstract

Determination of cell uptake pathways for tumor inhibitor lysyl oxidase propeptide

Cited by 27 publications

References 120 publications

Macropinocytosis activated by oncogenic Dbl enables specific targeted delivery of Tat/pDNA nano-complexes into ovarian cancer cells

Macropinocytosis activated by oncogenic Dbl enables specific targeted delivery of Tat/pDNA nano-complexes into ovarian cancer cells

Functional importance of lysyl oxidase family propeptide regions

Advances in liquid biopsy on-chip for cancer management: Technologies, biomarkers, and clinical analysis

Contact Info

Product

Resources

About