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.
authors.affiliation: Department of Biosystems & Biomaterials Science and Engineering, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Shambhavi
authors.initials: S
authors.lastname: Pandey
authors.affiliation: Department of Biosystems & Biomaterials Science and Engineering, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Garg
authors.affiliation: Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Somin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Oral and Maxillofacial Surgery and Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-774, Republic of Korea.
authors.forename: Han-Wool
authors.initials: HW
authors.lastname: Choung
authors.affiliation: Department of Otalaryngology, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
authors.forename: Yun-Hoon
authors.initials: YH
authors.lastname: Choung
authors.affiliation: Department of Oral and Maxillofacial Surgery and Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-774, Republic of Korea. Electronic address: choungph@snu.ac.kr.
authors.forename: Pill-Hoon
authors.initials: PH
authors.lastname: Choung
authors.affiliation: Department of Biosystems & Biomaterials Science and Engineering, Seoul National University, Seoul 151-921, Republic of Korea; Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea. Electronic address: jchung@snu.ac.kr.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D020868:Gene Silencing; D005822:Genetic Vectors; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009711:Nucleotides / Q000096:biosynthesis*; D011073:Polyamines / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D025101:Vitamin B 6 / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009711:Nucleotides; D011073:Polyamines; D011091:Polyesters; D034741:RNA, Small Interfering; C516446:poly(caprolactone-block-ethyleneimine); D025101:Vitamin B 6; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human
keywords: Membrane carrier; Poly(ester amine); Serine hydroxymethyltransferase; Vitamin B(6); siRNA