Involvement of glutathione and glutathione metabolizing enzymes in human colorectal cancer cell lines and tissues

Kim,Areum Daseul; Zhang,Rui; Han,Xia; Kang,Kyoung Ah; Piao,Mei Jing; Maeng,Young Hee; Chang,Weon Young; Hyun,Jin Won

doi:10.3892/mmr.2015.3902

Involvement of glutathione and glutathione metabolizing enzymes in human colorectal cancer cell lines and tissues

Authors:
- Areum Daseul Kim
- Rui Zhang
- Xia Han
- Kyoung Ah Kang
- Mei Jing Piao
- Young Hee Maeng
- Weon Young Chang
- Jin Won Hyun
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Affiliations: Department of Biochemistry, School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju 690‑756, Republic of Korea
Published online on: June 9, 2015 https://doi.org/10.3892/mmr.2015.3902
Pages: 4314-4319

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Abstract

Reduced glutathione (GSH) is an abundant tripeptide present in the majority of cell types. GSH is highly reactive and is often conjugated to other molecules, via its sulfhydryl moiety. GSH is synthesized from glutamic acid, cysteine, and glycine via two sequential ATP‑consuming steps, which are catalyzed by glutamate cysteine ligase (GCL) and GSH synthetase (GSS). However, the role of GSH in cancer remains to be elucidated. The present study aimed to determine the levels of GSH and GSH synthetic enzymes in human colorectal cancer. The mRNA and protein expression levels of GSH, the catalytic subunit of GCL (GCLC) and GSS were significantly higher in the following five colon cancer cell lines: Caco‑2, SNU‑407, SNU‑1033, HCT‑116, and HT‑29, as compared with the normal colon cell line, FHC. Similarly, in 9 out of 15 patients with colon cancer, GSH expression levels were higher in tumor tissue, as compared with adjacent normal tissue. In addition, the protein expression levels of GCLC and GSS were higher in the tumor tissue of 8 out of 15, and 10 out of 15 patients with colon cancer respectively, as compared with adjacent normal tissue. Immunohistochemical analyses confirmed that GCLC and GSS were expressed at higher levels in colon cancer tissue, as compared with normal mucosa. Since GSH and GSH metabolizing enzymes are present at elevated levels in colonic tumors, they may serve as clinically useful biomarkers of colon cancer, and/or targets for anti-colon cancer drugs.

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1	Lu SC: Regulation of glutathione synthesis. Mol Aspects Med. 30:42–59. 2009. View Article : Google Scholar :
2	Lu SC: Glutathione synthesis. Biochim Biophys Acta. 1830:3143–3153. 2013. View Article : Google Scholar :
3	Huang HC, Nguyen T and Pickett CB: Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Proc Natl Acad Sci USA. 97:12475–12480. 2000. View Article : Google Scholar : PubMed/NCBI
4	Kuo MT: Redox regulation of multidrug resistance in cancer chemotherapy: Molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal. 11:99–133. 2009. View Article : Google Scholar :
5	Nguyen LN, Munshi A, Hobbs ML, Story MD and Meyn RD Jr: Paclitaxel restores radiation-induced apoptosis in a bcl-2-expressing, radiation-resistant lymphoma cell line. Int J Radiat Oncol Biol Phys. 49:1127–1132. 2001. View Article : Google Scholar : PubMed/NCBI
6	Vukovic V, Nicklee T and Hedley DW: Microregional heterogeneity of non-protein thiols in cervical carcinomas assessed by combined use of HPLC and fluorescence image analysis. Clin Cancer Res. 6:1826–1832. 2000.PubMed/NCBI
7	Vukovic V, Nicklee T and Hedley DW: Differential effects of buthionine sulphoximine in hypoxic and non-hypoxic regions of human cervical carcinoma xenografts. Radiother Oncol. 60:69–73. 2001. View Article : Google Scholar : PubMed/NCBI
8	Herceg Z: Epigenetics and cancer: Towards an evaluation of the impact of environmental and dietary factors. Mutagenesis. 22:91–103. 2007. View Article : Google Scholar : PubMed/NCBI
9	Arvelo F, Sojo F and Cotte C: Biology of colorectal cancer. Ecancermedicalscience. 9:5202015. View Article : Google Scholar : PubMed/NCBI
10	Singh S: Cytoprotective and regulatory functions of glutathione S-transferases in cancer cell proliferation and cell death. Cancer Chemother Pharmacol. 75:1–15. 2015. View Article : Google Scholar
11	Dizdaroglu M: Oxidatively induced DNA damage and its repair in cancer. Mutat Res Rev Mutat Res. 763:212–245. 2015. View Article : Google Scholar : PubMed/NCBI
12	Laborde E: Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death. Cell Death Differ. 17:1373–1380. 2010. View Article : Google Scholar : PubMed/NCBI
13	Joncourt F, Oberli-Schrämmli AE, Stadler M, Buser K, Franscini L, Fey MF and Cerny T: Patterns of drug resistance parameters in adult leukemia. Leuk Lymphoma. 17:101–109. 1995. View Article : Google Scholar : PubMed/NCBI
14	Perry RR, Mazetta JA, Levin M and Barranco SC: Glutathione levels and variability in breast tumors and normal tissue. Cancer. 72:783–787. 1993. View Article : Google Scholar : PubMed/NCBI
15	Jardim BV, Moschetta MG, Leonel C, Gelaleti GB, Regiani VR, Ferreira LC, Lopes JR and Zuccari DA: Glutathione and glutathione peroxidase expression in breast cancer: An immunohistochemical and molecular study. Oncol Rep. 30:1119–1128. 2013.PubMed/NCBI
16	Cook JA, Pass HI, Iype SN, Friedman N, DeGraff W, Russo A and Mitchell JB: Cellular glutathione and thiol measurements from surgically resected human lung tumor and normal lung tissue. Cancer Res. 51:4287–4294. 1991.PubMed/NCBI
17	Oberli-Schrämmli AE, Joncourt F, Stadler M, et al: Parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA alkyltransferase and P-glycoprotein as indicators of drug resistance in tumor and normal lung of patients with lung cancer. Int J Cancer. 59:629–636. 1994. View Article : Google Scholar : PubMed/NCBI
18	Sies H: Glutathione and its role in cellular functions. Free Radic Biol Med. 27:916–921. 1999. View Article : Google Scholar : PubMed/NCBI
19	Soini Y, Karihtala P, Mäntyniemi A, Turunen N, Pääkko P and Kinnula V: Glutamate-L-cysteine ligase in breast carcinomas. Histopathology. 44:129–135. 2004. View Article : Google Scholar : PubMed/NCBI
20	Mougiakakos D, Okita R, Ando T, et al: High expression of GCLC is associated with malignant melanoma of low oxidative phenotype and predicts a better prognosis. J Mol Med (Berl). 90:935–944. 2012. View Article : Google Scholar
21	Leonel C, Gelaleti GB, Jardim BV, et al: Expression of glutathione, glutathione peroxidase and glutathione S-transferase pi in canine mammary tumors. BMC Vet Res. 10:492014. View Article : Google Scholar : PubMed/NCBI
22	Bailey HH, Gipp JJ, Ripple M, Wilding G and Mulcahy RT: Increase in gamma-glutamylcysteine synthetase activity and steady-state messenger RNA levels in melphalan-resistant DU-145 human prostate carcinoma cells expressing elevated glutathione levels. Cancer Res. 52:5115–5118. 1992.PubMed/NCBI