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Nucleotide biosynthesis arrest by silencing SHMT1 function via vitamin B6-coupled vector and effects on tumor growth inhibition

Paper ID Volume ID Publish Year Pages File Format Full-Text
6043 455 2014 11 PDF Available
Title
Nucleotide biosynthesis arrest by silencing SHMT1 function via vitamin B6-coupled vector and effects on tumor growth inhibition
Abstract

Serine hydroxymethyltransferase isoforms (SHMT1 & SHMT2α), which serve as scaffold protein for the formation of a multi-enzyme complex and generate one-carbon unit for the de novo thymidylate biosynthesis pathway during DNA synthesis, are vitamin B6 (VB6)-dependent enzyme. Cancer cells with high proliferation intensity need increased SHMT activation which enforces the facilitated-diffusion of VB6 for the continuous functioning of thymidylate synthase cycle. Therefore, SHMT knockdown presents an alternative approach to prevent DNA synthesis in cancer cells; however, its potential to inhibit cancer growth remains unknown so far. Here we demonstrated that VB6 coupled to poly(ester amine) (VBPEA) enforces a high level of VTC (VB6-transporting membrane carriers)-mediated endocytosis of the complexed SHMT1 siRNA (siSHMT1) to interrupt the thymidylate biosynthesis pathway of cancer cells. The detrimental effect of SHMT1 knockdown on the disintegration of multi-enzyme complex resulted in cell cycle arrest and a decrease in cell's genomic DNA content, leading to enhanced apoptotic events in cancer cells. A reduction in tumor size was observed with constant SHMT1 suppression in xenograft mice. This study illustrates how silencing the SHMT1 expression inhibits cancer growth and the increased VB6 channeling for sustenance of cancer cells promotes VB6-coupled vector to elicit enhanced delivery of siSHMT1.

Keywords
Serine hydroxymethyltransferase; Vitamin B6; Poly(ester amine); Membrane carrier; siRNA
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Nucleotide biosynthesis arrest by silencing SHMT1 function via vitamin B6-coupled vector and effects on tumor growth inhibition
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Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 35, Issue 34, November 2014, Pages 9332–9342
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us