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.
Highlights
SHMT2 has been shown to be a crucial factor in the serine/ glycine metabolism of several cancer cell types, including colon and breast, and represents a hot target for selective anticancer drugs.[12]
In this study we show that in addition to SHMT2, SHMT1 is overexpressed in samples from lung cancer patients and lung cancer cell lines, suggesting that, at least in this type of tumor, SHMT1 might have a relevant role
We demonstrate that SHMT1 knockdown in lung cancer cells leads to cell cycle arrest and, more importantly, to p53-dependent apoptosis
Summary
SHMT2 has been shown to be a crucial factor in the serine/ glycine metabolism of several cancer cell types, including colon and breast, and represents a hot target for selective anticancer drugs.[12]. We demonstrate that SHMT1 is upregulated in patientderived lung cancer tissue samples, there is a crosstalk among SHMT1 and 2 and, unlike other cancer cell types, the downregulation of SHMT1 in lung cancer cell lines through RNAi induces cell cycle arrest and apoptosis, the latter with the involvement of p53. Our results demonstrate that the antitumor effect induced by SHMT RNAi is not because of serine or glycine starvation, but is mediated by the increased misincorporation of uracil in the genomic DNA possibly because of dTMP loss. Our data open the possibility to target cytoplasmic SHMT1 to treat lung cancer patients
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