Enzymes involved in folate metabolism and its implication for cancer treatment
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
BACKGROUND/OBJECTIVES: Folate plays a critical role in DNA synthesis and methylation. Intracellular folate homeostasis is maintained by the enzymes folylpolyglutamate synthase (FPGS) and γ-glutamyl hydrolase (GGH). FPGS adds glutamate residues to folate upon its entry into the cell through a process known as polyglutamylation to enhance folate retention in the cell and to maintain a steady supply of utilizable folate derivatives for folate-dependent enzyme reactions. Thereafter, GGH catalyzes the hydrolysis of polyglutamylated folate into monoglutamylated folate, which can subsequently be exported from the cell. The objective of this review is to summarize the scientific evidence available on the effects of intracellular folate homeostasis-associated enzymes on cancer chemotherapy. METHODS: This review discusses the effects of FPGS and GGH on chemosensitivity to cancer chemotherapeutic agents such as antifolates, such as methotrexate, and 5-fluorouracil. RESULTS AND DISCUSSION: Polyglutamylated (anti)folates are better substrates for intracellular folate-dependent enzymes and retained for longer within cells. In addition to polyglutamylation of (anti)folates, FPGS and GGH modulate intracellular folate concentrations, which are an important determinant of chemosensitivity of cancer cells toward chemotherapeutic agents. Therefore, FPGS and GGH affect chemosensitivity to antifolates and 5-fluorouracil by altering intracellular retention status of antifolates and folate cofactors such as 5,10-methylenetetrahydrofolate, subsequently influencing the cytotoxic effects of 5-fluorouracil, respectively. Generally, high FPGS and/or low GGH activity is associated with increased chemosensitivity of cancer cells to methotrexate and 5-fluorouracil, while low FPGS and/or high GGH activity seems to correspond to resistance to these drugs. Further preclinical and clinical studies elucidating the pharmocogenetic ramifications of these enzyme-induced changes are warranted to provide a framework for developing rational, effective, safe, and customized chemotherapeutic practices.
Abstract
BACKGROUND/OBJECTIVES: Folate plays a critical role in DNA synthesis and methylation. Intracellular folate homeostasis is maintained by the enzymes folylpolyglutamate synthase (FPGS) and γ-glutamyl hydrolase (GGH). FPGS adds glutamate residues to folate upon its entry into the cell through a process known as polyglutamylation to enhance folate retention in the cell and to maintain a steady supply of utilizable folate derivatives for folate-dependent enzyme reactions. Thereafter, GGH catalyzes the hydrolysis of polyglutamylated folate into monoglutamylated folate, which can subsequently be exported from the cell. The objective of this review is to summarize the scientific evidence available on the effects of intracellular folate homeostasis-associated enzymes on cancer chemotherapy. METHODS: This review discusses the effects of FPGS and GGH on chemosensitivity to cancer chemotherapeutic agents such as antifolates, such as methotrexate, and 5-fluorouracil. RESULTS AND DISCUSSION: Polyglutamylated (anti)folates are better substrates for intracellular folate-dependent enzymes and retained for longer within cells. In addition to polyglutamylation of (anti)folates, FPGS and GGH modulate intracellular folate concentrations, which are an important determinant of chemosensitivity of cancer cells toward chemotherapeutic agents. Therefore, FPGS and GGH affect chemosensitivity to antifolates and 5-fluorouracil by altering intracellular retention status of antifolates and folate cofactors such as 5,10-methylenetetrahydrofolate, subsequently influencing the cytotoxic effects of 5-fluorouracil, respectively. Generally, high FPGS and/or low GGH activity is associated with increased chemosensitivity of cancer cells to methotrexate and 5-fluorouracil, while low FPGS and/or high GGH activity seems to correspond to resistance to these drugs. Further preclinical and clinical studies elucidating the pharmocogenetic ramifications of these enzyme-induced changes are warranted to provide a framework for developing rational, effective, safe, and customized chemotherapeutic practices.
참고문헌 (81)
- Shane B, "Folate in Health and Disease", pp.1~24 (2010), CRC Press
- Gropper SAS, "Advanced Nutrition and Human Metabolism", pp.2009, Wadsworth
- Kim YI, "Role of folate in colon cancer development and progression", J Nutr, 133, pp.3731S~3739S (2003)
- Kim YI, "Folate and carcinogenesis : evidence, mechanisms, and implications", J Nutr Biochem, 10, pp.66~88 (1999)
- Kim YI, "Folate and colorectal cancer : an evidence-based critical review", Mol Nutr Food Res, 51, pp.267~292 (2007)
- Kim YI, "Folic acid supplementation and cancer risk : point", Cancer Epidemiol Biomarkers Prev, 17, pp.2220~2225 (2008)
- 박영미, "Circulating folate levels and colorectal adenoma: a case-control study and a meta-analysis", Nutrition Research and Practice, 11(5), pp.419~429 (2017), 한국영양학회
- Figueiredo JC, "Folic acid and risk of prostate cancer : results from a randomized clinical trial", J Natl Cancer Inst, 101, pp.432~435 (2009)
- Hirsch S, "Colon cancer in Chile before and after the start of the flour fortification program with folic acid", Eur J Gastroenterol Hepatol, 21, pp.436~439 (2009)
- Mason JB, "A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles : a hypothesis", Cancer Epidemiol Biomarkers Prev, 16, pp.1325~1329 (2007)
- Bailey RL, "Total folate and folic acid intake from foods and dietary supplements in the United States : 2003-2006", Am J Clin Nutr, 91, pp.231~237 (2010)
- Shakur YA, "A comparison of micronutrient inadequacy and risk of high micronutrient intakes among vitamin and mineral supplement users and nonusers in Canada", J Nutr, 142, pp.534~540 (2012)
- Velicer CM, "Vitamin and mineral supplement use among US adults after cancer diagnosis : a systematic review", J Clin Oncol, 26, pp.665~673 (2008)
- Holmes RS, "Use of folic acid-containing supplements after a diagnosis of colorectal cancer in the Colon Cancer Family Registry", Cancer Epidemiol Biomarkers Prev, 19, pp.2023~2034 (2010)
- Satia JA, "Longitudinal changes in lifestyle behaviors and health status in colon cancer survivors", Cancer Epidemiol Biomarkers Prev, 13, pp.1022~1031 (2004)
- Sandler RS, "Use of vitamins, minerals, and nutritional supplements by participants in a chemoprevention trial", Cancer, 91, pp.1040~1045 (2001)
- Assaraf YG, "The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis", Drug Resist Updat, 9, pp.227~246 (2006)
- Hooijberg JH, "Multidrug resistance proteins and folate supplementation : therapeutic implications for antifolates and other classes of drugs in cancer treatment", Cancer Chemother Pharmacol, 58, pp.1~12 (2006)
- Porcelli L, "The impact of folate status on the efficacy of colorectal cancer treatment", Curr Drug Metab, 12, pp.975~984 (2011)
- Assaraf YG, "Molecular basis of antifolate resistance", Cancer Metastasis Rev, 26, pp.153~181 (2007)
- Moran RG, "Roles of folylpoly-gamma-glutamate synthetase in therapeutics with tetrahydrofolate antimetabolites : an overview", Semin Oncol, 26, pp.24~32 (1999)
- Kamen B, "Folate and antifolate pharmacology", Semin Oncol, 24, pp.S18~S30 (1997)
- Zhao R, "Resistance to antifolates", Oncogene, 22, pp.7431~7457 (2003)
- Calvert H, "An overview of folate metabolism : features relevant to the action and toxicities of antifolate anticancer agents", Semin Oncol, 26, pp.3~10 (1999)
- Kremer JM, "Toward a better understanding of methotrexate", Arthritis Rheum, 50, pp.1370~1382 (2004)
- Grem JL, "5-Fluorouracil : forty-plus and still ticking. A review of its preclinical and clinical development", Invest New Drugs, 18, pp.299~313 (2000)
- Longley DB, "5-fluorouracil : mechanisms of action and clinical strategies", Nat Rev Cancer, 3, pp.330~338 (2003)
- Radparvar S, "Effect of polyglutamylation of 5, 10-methylenetetrahydrofolate on the binding of 5-fluoro-2′-deoxyuridylate to thymidylate synthase purified from a human colon adenocarcinoma xenograft", Biochem Pharmacol, 38, pp.335~342 (1989)
- Cho RC, "Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells", Mol Cancer Ther, 6, pp.2909~2920 (2007)
- Kim SE, "γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate", Br J Cancer, 109, pp.2175~2188 (2013)
- Sakamoto E, "Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity", Biochem Biophys Res Commun, 365, pp.801~807 (2008)
- Sharma S, "Epigenetics in cancer", Carcinogenesis, 31, pp.27~36 (2010)
- McGuire JJ, "Enzymatic synthesis and function of folylpolyglutamates", Mol Cell Biochem, 38, pp.19~48 (1981)
- Cichowicz DJ, "Mammalian folylpoly-gamma-glutamate synthetase. 2. Substrate specificity and kinetic properties", Biochemistry, 26, pp.513~521 (1987)
- Cook JD, "Mammalian folylpoly-gamma-glutamate synthetase. 4. In vitro and in vivo metabolism of folates and analogues and regulation of folate homeostasis", Biochemistry, 26, pp.530~539 (1987)
- Kim JS, "Regulation of folate and one-carbon metabolism in mammalian cells. IV. Role of folylpoly-gammaglutamate synthetase in methotrexate metabolism and cytotoxicity", J Biol Chem, 268, pp.21680~21685 (1993)
- Aghi M, "Folylpolyglutamyl synthetase gene transfer and glioma antifolate sensitivity in culture and in vivo", J Natl Cancer Inst, 91, pp.1233~1241 (1999)
- Pizzorno G, "Impaired polyglutamylation of methotrexate as a cause of resistance in CCRF-CEM cells after short-term, high-dose treatment with this drug", Cancer Res, 48, pp.2149~2155 (1988)
- McCloskey DE, "Decreased folylpolyglutamate synthetase activity as a mechanism of methotrexate resistance in CCRF-CEM human leukemia sublines", J Biol Chem, 266, pp.6181~6187 (1991)
- Mauritz R, "Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis", Biochem Pharmacol, 63, pp.105~115 (2002)
- Liani E, "Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines", Int J Cancer, 103, pp.587~599 (2003)
- Zhao R, "Molecular analysis of murine leukemia cell lines resistant to 5, 10-dideazatetrahydrofolate identifies several amino acids critical to the function of folylpolyglutamate synthetase", J Biol Chem, 275, pp.26599~26606 (2000)
- Roy K, "Posttranscriptionally mediated decreases in folylpolyglutamate synthetase gene expression in some folate analogue-resistant variants of the L1210 cell. Evidence for an altered cognate mRNA in the variants affecting the rate of de novo synthesis of the enzyme", J Biol Chem, 272, pp.6903~6908 (1997)
- Romanini A, "Role of folylpolyglutamates in biochemical modulation of fluoropyrimidines by leucovorin", Cancer Res, 51, pp.789~793 (1991)
- Wang FS, "Decreased folylpolyglutamate synthetase expression : a novel mechanism of fluorouracil resistance", Cancer Res, 53, pp.3677~3680 (1993)
- Chéradame S, "Relevance of tumoral folylpolyglutamate synthetase and reduced folates for optimal 5-fluorouracil efficacy : experimental data", Eur J Cancer, 33, pp.950~959 (1997)
- Sohn KJ, "Effects of folylpolyglutamate synthetase modulation on chemosensitivity of colon cancer cells to 5-fluorouracil and methotrexate", Gut, 53, pp.1825~1831 (2004)
- Backus HH, "Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates", Int J Cancer, 87, pp.771~778 (2000)
- Zhao R, "Marked suppression of the activity of some, but not all, antifolate compounds by augmentation of folate cofactor pools within tumor cells", Biochem Pharmacol, 61, pp.857~865 (2001)
- Odin E, "Altered gene expression of folate enzymes in adjacent mucosa is associated with outcome of colorectal cancer patients", Clin Cancer Res, 9, pp.6012~6019 (2003)
- Wettergren Y, "Low expression of reduced folate carrier-1 and folylpolyglutamate synthase correlates with lack of a deleted in colorectal carcinoma mRNA splice variant in normal-appearing mucosa of colorectal carcinoma patients", Cancer Detect Prev, 29, pp.348~355 (2005)
- Oppeneer SJ, "Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese Health Study", Mol Genet Metab, 105, pp.73~78 (2012)
- van der Straaten RJ, "Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients", Pharmacogenomics, 8, pp.141~150 (2007)
- Liu SG, "FPGS rs1544105 polymorphism is associated with treatment outcome in pediatric B-cell precursor acute lymphoblastic leukemia", Cancer Cell Int, 13, pp.107~ (2013)
- Sharma S, "Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians", Pharmacogenet Genomics, 19, pp.823~828 (2009)
- Leclerc GJ, "Folylpolyglutamate synthetase gene transcription is regulated by a multiprotein complex that binds the TEL-AML1 fusion in acute lymphoblastic leukemia", Leuk Res, 34, pp.1601~1609 (2010)
- Leclerc GJ, "Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia : implications for combination therapy", Leukemia, 24, pp.552~562 (2010)
- Kim SE, "Effects of folylpolyglutamate synthase modulation on global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells", J Nutr Biochem, 29, pp.27~35 (2016)
- Waltham MC, "gamma-Glutamyl hydrolase from human sarcoma HT-1080 cells : characterization and inhibition by glutamine antagonists", Mol Pharmacol, 51, pp.825~832 (1997)
- Longo GS, "Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells", Blood, 90, pp.1241~1245 (1997)
- Rots MG, "Role of folylpolyglutamate synthetase and folylpolyglutamate hydrolase in methotrexate accumulation and polyglutamylation in childhood leukemia", Blood, 93, pp.1677~1683 (1999)
- Li WW, "Increased activity of gamma-glutamyl hydrolase in human sarcoma cell lines : a novel mechanism of intrinsic resistance to methotrexate(MTX)", Adv Exp Med Biol, 338, pp.635~638 (1993)
- Pizzorno G, "Multifactorial resistance to 5, 10-dideazatetrahydrofolic acid in cell lines derived from human lymphoblastic leukemia CCRF-CEM", Cancer Res, 55, pp.566~573 (1995)
- Rhee MS, "Acquisition of resistance to antifolates caused by enhanced gamma-glutamyl hydrolase activity", Cancer Res, 53, pp.2227~2230 (1993)
- Schneider E, "Gamma-glutamyl hydrolase and drug resistance", Clin Chim Acta, 374, pp.25~32 (2006)
- Yao R, "Effects of gamma-glutamyl hydrolase on folyl and antifolylpolyglutamates in cultured H35 hepatoma cells", Mol Pharmacol, 48, pp.505~511 (1995)
- O'Connor BM, "Secretion of gamma-glutamyl hydrolase in vitro", Cancer Res, 51, pp.3874~3881 (1991)
- Nimec Z, "Regulatory aspects of the glutamylation of methotrexate in cultured hepatoma cells", Arch Biochem Biophys, 226, pp.671~680 (1983)
- Galivan J, "Hormonal alteration of methotrexate and folate polyglutamate formation in cultured hepatoma cells", Arch Biochem Biophys, 230, pp.355~362 (1984)
- Galivan J, "Insulin-dependent suppression in glutamyl hydrolase activity and elevated cellular methotrexate polyglutamates", Biochem Pharmacol, 50, pp.1659~1663 (1995)
- Samowitz WS, "Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer", Gastroenterology, 129, pp.837~845 (2005)
- Iacopetta B, "Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients : is the CpG island methylator phenotype the 5-fluorouracil-responsive subgroup", Int J Clin Oncol, 13, pp.498~503 (2008)
- Kawakami K, "Low expression of gammaglutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype", Br J Cancer, 98, pp.1555~1561 (2008)
- Chave KJ, "Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms", Gene, 319, pp.167~175 (2003)
- Hashiguchi M, "Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population", J Pharm Health Care Sci, 2, pp.35~ (2016)
- Dervieux T, "Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis", Pharmacogenetics, 14, pp.733~739 (2004)
- Kim K, "XRCC1Arginine194Tryptophan and GGH-401Cytosine", Thymine polymorphisms are associated with response to platinum-based neoadjuvant chemotherapy in cervical cancer, 2008, pp.111, 509~515
- Cheng Q, "A substrate specific functional polymorphism of human gamma-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells", Pharmacogenetics, 14, pp.557~567 (2004)
- Cheng Q, "Epigenetic regulation of human gamma-glutamyl hydrolase activity in acute lymphoblastic leukemia cells", Am J Hum Genet, 79, pp.264~274 (2006)
- Li Y, "Methylation level of CpG islands in GGH gene promoter in pediatric acute leukemia", PLoS One, 12, pp.e0173472~ (2017)
- Kim SE, "γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells", Genes Nutr, 10, pp.444~ (2015)