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∗ Corresponding author.
1 The equal first author contribution by Dr. Dong-Joon Min and Suleyman Vural.
the NCI-60 cancer cell line panel. Pretreatment expression levels were correlated among many one-carbon metabolism genes. Expression of several folate genes was strongly associated with expression of multiple components of drug target pathways. Molecular mechanisms underlying associations of one-carbon metabolism gene with drug response require further investigation.
Keywords One-carbon metabolism, Folate, Cancer treatment, Drug sensitivity, Gene expression.
Folate-mediated one-carbon metabolism (OCM), which involves folate and methionine cycles, regulates cellular nutrient status and redistribution of one-carbon units into reactions and processes that are vital for cellular functions [1,2]. One-carbon units generated from folic Ferrostatin-1 and amino acids are used for cellular biosynthesis, regulation of redox status, nucleic acid and protein methylation, and genome maintenance, which are necessary for cell growth and sur-vival [1,3]. The folate cycle involves multiple biosynthetic reactions in the cytoplasm, mitochondria, and the nucleus [1,4,5]. These reactions lead to biosynthesis of critical com-ponents of cell function including synthesis of nucleotides, ATP and NADPH, and biosynthesis and interconversions of amino acids (e.g., serine, glycine, methionine, and histidine), and they also affect cellular methylation processes [6–8].
An ample amount of evidence has been accumulated that indicates that the genes involved in folate cycle reactions or folate transport play important roles in cancer risk and progression [1,8]. The OCM processes are critically impor-tant for the metabolic rewiring of cancer cells . Numerous studies have documented that expression patterns and genetic variation of folate metabolism-related genes, dietary folate status, and changes in the folate cycle reactions and in DNA methylation, synthesis, and repair are associated with cancer risk and with in vitro and clinical response to drug treatment [4,8–14]. Inhibition of the components of the folate cycle can reduce growth and proliferation of malignant cells and increase DNA damage [15–17]. These mechanisms are suppressed by the action of anti-folate cancer drugs [6,15]. Increased levels of reactive oxygen species (ROS) under oncogenic transformation promote cancer cell proliferation with active cellular synthesis and methylation, but they may also lead to DNA damage-induced cell death if ROS levels are too high [16,17]. OCM reactions are critical for carcinogene-sis, as they support increased proliferation of cancer cells by enabling high levels of cellular synthesis of critical molecular components, regulating redox reactions, and suppressing apoptosis by controlling the ROS levels [2,16,17].
Drug resistance of cancer cells may involve many biolog-ical processes, e.g. drug efflux, drug inactivation, drug tar-get modification, DNA damage repair, and apoptosis inhibition . A number of anticancer drugs may be activated and their targets could be modified by metabolic processes (18]. OCM reactions may affect drug efficacy through their effect on tu-mor growth and proliferation, their connection to other cellular metabolic reactions in the cell and to the processes of amino acid biosynthesis, nucleotide biosynthesis and DNA repair, and through their contribution to DNA and protein methyla-tion processes which affect the expression of genes related to drug activation and drug targeting [1,8,13,19,20].
In an earlier study of five antitumor agents, we found an association between post-treatment expression changes of
several genes involved in folate metabolism or transport with sensitivity or resistance to doxorubicin, paclitaxel, and cis-platin . Given the importance of OCM reactions in growth and survival of cancer cells, we hypothesized that the re-sponse of cancer cells to drug treatment may be influenced by pretreatment levels of genes that are involved in folate transport and in OCM reactions. We examined whether pre-treatment expression levels of some of the OCM genes were associated with sensitivity to a variety of antitumor agents, and whether expression levels of certain OCM genes could potentially be used as biomarkers associated with drug re-sponse. To study possible molecular mechanisms underly-ing such associations with drug response, we also examined whether pretreatment expression levels of OCM genes in tu-mor cells were correlated with each other and with expression levels of molecular components of drug target pathways.
Materials and methods
The datasets analyzed in this study are publicly available on-line from the Cancer Cell Line Encyclopedia (CCLE), Ge-nomics of Drug Sensitivity in Cancer (GDSC), and Cellminer-CDB resources [22–25].