title: SHMT1 knockdown induces apoptosis in lung cancer cells by causing uracil misincorporation.
abstract: Reprogramming of cellular metabolism towards de novo serine production fuels the growth of cancer cells, providing essential precursors such as amino acids and nucleotides and controlling the antioxidant and methylation capacities of the cell. The enzyme serine hydroxymethyltransferase (SHMT) has a key role in this metabolic shift, and directs serine carbons to one-carbon units metabolism and thymidilate synthesis. While the mitochondrial isoform of SHMT (SHMT2) has recently been identified as an important player in the control of cell proliferation in several cancer types and as a hot target for anticancer therapies, the role of the cytoplasmic isoform (SHMT1) in cancerogenesis is currently less defined. In this paper we show that SHMT1 is overexpressed in tissue samples from lung cancer patients and lung cancer cell lines, suggesting that, in this widespread type of tumor, SHMT1 plays a relevant role. We show that SHMT1 knockdown in lung cancer cells leads to cell cycle arrest and, more importantly, to p53-dependent apoptosis. Our data demonstrate that the induction of apoptosis does not depend on serine or glycine starvation, but is because of the increased uracil accumulation during DNA replication.
authors.affiliation: Department of Biochemical Sciences, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Paone
authors.affiliation: Department of Biochemical Sciences, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marani
authors.affiliation: Department of Biochemical Sciences, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Fiascarelli
authors.affiliation: Department of Biochemical Sciences, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Rinaldo
authors.affiliation: Department of Biochemical Sciences, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Giardina
authors.affiliation: Department of Biochemical Sciences, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Contestabile
authors.affiliation: Department of Biochemical Sciences, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Paiardini
authors.affiliation: Department of Biochemical Sciences, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Cutruzzolà
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D012696:Glycine Hydroxymethyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014498:Uracil / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D012694:Serine; D014498:Uracil; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human