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.

• Authors: Shambhavi Pandey, Pankaj Garg, Somin Lee, Han-Wool Choung, Yun-Hoon Choung, Pill-Hoon Choung, Jong Hoon Chung
• Journal: Biomaterials (Biomaterials) Vol. 35 Issue 34 Pg. 9332-42 (Nov 2014) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 25132602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Nucleotides
• Polyamines
• Polyesters
• RNA, Small Interfering
• poly(caprolactone-block-ethyleneimine)
• Vitamin B 6
• Glycine Hydroxymethyltransferase
• SHMT protein, human

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Endocytosis (drug effects)
• Gene Silencing
• Genetic Vectors
• Glycine Hydroxymethyltransferase (genetics, metabolism)
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasms (drug therapy, genetics)
• Nucleotides (biosynthesis)
• Polyamines (chemistry)
• Polyesters (chemistry)
• RNA, Small Interfering (genetics, metabolism)
• Vitamin B 6 (pharmacology)
• Xenograft Model Antitumor Assays