Altered glutamate cysteine ligase expression and activity in renal cell carcinoma

Li,Monong; Zhang,Zongliang; Yuan,Jiangshui; Zhang,Yanlun; Jin,Xunbo

doi:10.3892/br.2014.359

Altered glutamate cysteine ligase expression and activity in renal cell carcinoma

Authors:
- Monong Li
- Zongliang Zhang
- Jiangshui Yuan
- Yanlun Zhang
- Xunbo Jin
View Affiliations

Affiliations: School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China, Qingdao Municipal Hospital, Qingdao, Shandong 266071, P.R. China
Published online on: September 9, 2014 https://doi.org/10.3892/br.2014.359
Pages: 831-834

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Oxidative stress has been linked to the progression of mutations and cancer. Increased glutathione (GSH) contents have been observed in a number of different human cancer tissues. GSH is synthesized de novo in a two‑step process catalyzed by glutamate cysteine ligase (GCL). The present study aimed to investigate whether GCL was associated with renal cell carcinoma (RCC). The protein expression levels of the GCL subunits (catalytic subunit, GCLc; and modulatory subunit, GCLm) and GCL activity were examined in renal cancer tissue. A total of 46 patients fulfilling the RCC criteria of the World Health Organization, revised in 2004, were enrolled. The tumor and adjacent tissues were sampled from all the subjects by surgery. The study demonstrated that GCLc and GCLm protein expression and the GCL activity were significantly increased in the tumor tissue from RCC patients. These results indicate that increased expression and enzymatic activity of GCL is closely associated with RCC and thus, this suggests an important role for GSH in the pathogenesis of RCC.

View Figures

View References

1	Shah D, Aggarwal A, Bhatnagar A, Kiran R and Wanchu A: Association between T lymphocyte sub-sets apoptosis and peripheral blood mononuclear cells oxidative stress in systemic lupus erythematosus. Free Radic Res. 45:559–567. 2011. View Article : Google Scholar : PubMed/NCBI
2	Lusini L, Tripodi SA, Rossi R, et al: Altered glutathione anti-oxidant metabolism during tumor progression in human renal-cell carcinoma. Int J Cancer. 91:55–59. 2001. View Article : Google Scholar : PubMed/NCBI
3	Ames BN, Shigenaga MK and Gold LS: DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis. Environ Health Perspect. 101(Suppl 5): 35–44. 1993. View Article : Google Scholar : PubMed/NCBI
4	Moller P and Wallin H: Adduct formation, mutagenesis and nucleotide excision repair of DNA damage produced by reactive oxygen species and lipid peroxidation product. Mutat Res. 410:271–290. 1998. View Article : Google Scholar : PubMed/NCBI
5	Kongara S and Karantza V: The interplay between autophagy and ROS in tumorigenesis. Front Oncol. 2:1712012. View Article : Google Scholar
6	Kryston TB, Georgiev AB, Pissis P and Georgakilas AG: Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res. 711:193–201. 2011. View Article : Google Scholar : PubMed/NCBI
7	Eltzschig HK and Carmeliet P: Hypoxia and inflammation. N Engl J Med. 364:656–665. 2011. View Article : Google Scholar : PubMed/NCBI
8	Yeh CC, Hou MF, Wu SH, et al: A study of glutathione status in the blood and tissues of patients with breast cancer. Cell Biochem Funct. 24:555–559. 2006. View Article : Google Scholar : PubMed/NCBI
9	Suess E, Malessa S, Ungersböck K, et al: Technetium-99m-d, l-hexaniethylpropyleneamine oxime (HMPAO) uptake and glutathione content in brain tumors. J Nucl Med. 32:1675–1681. 1991.PubMed/NCBI
10	Grubben MJ, van den Braak CC, Nagengast FM and Peters WH: Low colonic glutathione detoxification capacity in patients at risk for colon cancer. Eur J Clin Invest. 36:188–192. 2006. View Article : Google Scholar : PubMed/NCBI
11	Peters WH, van Schaik A, Peters JH and van Goor H: Oxidised- and total non-protein bound glutathione and related thiols in gallbladder bile of patients with various gastrointestinal disorders. BMC Gastroenterol. 7:72007. View Article : Google Scholar : PubMed/NCBI
12	Gupta A, Srivastava S, Prasad R, et al: Oxidative stress in non-small cell lung cancer patients after chemotherapy: association with treatment response. Respirology. 15:349–356. 2010. View Article : Google Scholar : PubMed/NCBI
13	Almadori G, Bussu F, Galli J, et al: Salivary glutathione and uric acid levels in patients with head and neck squamous cell carcinoma. Head Neck. 29:648–654. 2007. View Article : Google Scholar : PubMed/NCBI
14	Kearns PR, Pieters R, Rottier MM, Pearson AD and Hall AG: Raised blast glutathione levels are associated with an increased risk of relapse in childhood acute lymphocytic leukemia. Blood. 97:393–398. 2001. View Article : Google Scholar : PubMed/NCBI
15	Singh S, Khan AR and Gupta AK: Role of glutathione in cancer pathophysiology and therapeutic interventions. J Exp Ther Oncol. 9:303–316. 2012.PubMed/NCBI
16	Ziegler DM: Role of reversible oxidation-reduction of enzyme thiols-disulfides in metabolic regulation. Annu Rev Biochem. 54:305–329. 1985. View Article : Google Scholar : PubMed/NCBI
17	Huang CS, Chang LS, Anderson ME and Meister A: Catalytic and regulatory properties of the heavy subunit of rat kidney gamma-glutamylcysteine synthetase. J Biol Chem. 268:19675–19680. 1993.PubMed/NCBI
18	McConnachie LA, Mohar I, Hudson FN, et al: Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice. Toxicol Sci. 99:628–636. 2007. View Article : Google Scholar : PubMed/NCBI
19	Dalton TP, Dieter MZ, Yang Y, Shertzer HG and Nebert DW: Knockout of the mouse glutamate cysteine ligase catalytic subunit (Gclc) gene: embryonic lethal when homozygous, and proposed model for moderate glutathione deficiency when heterozygous. Biochem Biophys Res Commun. 279:324–329. 2000. View Article : Google Scholar
20	Iida T, Kijima H, Urata Y, et al: Hammerhead ribozyme against gamma-glutamylcysteine synthetase sensitizes human colonic cancer cells to cisplatin by down-regulating both the glutathione synthesis and the expression of multidrug resistance proteins. Cancer Gene Ther. 8:803–814. 2001. View Article : Google Scholar
21	Eble JN, Sauter G, Epstein JI and Sesterhenn IA: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. 1st edition. IARC Press; Lyon: pp. 12–43. 2004
22	Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL and Trotti A: AJCC Cancer Staging Manual. 7th edition. Springer; New York, NY: pp. 103–115. 2010
23	Chen CN, Brown-Borg HM, Rakoczy SG, Ferrington DA and Thompson LV: Aging impairs the expression of the catalytic subunit of glutamate cysteine ligase in soleus muscle under stress. J Gerontol A Biol Sci Med Sci. 65:129–137. 2010. View Article : Google Scholar : PubMed/NCBI
24	Franklin CC, Backos DS, Mohar I, White CC, Forman HJ and Kavanagh TJ: Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Mol Aspects Med. 30:86–98. 2009. View Article : Google Scholar : PubMed/NCBI
25	Locigno R and Castronovo V: Reduced glutathione system: role in cancer development, prevention and treatment (review). Int J Oncol. 19:221–236. 2001.PubMed/NCBI
26	Kern JC and Kehrer JP: Free radicals and apoptosis: relationships with glutathione, thioredoxin, and the BCL family of proteins. Front Biosci. 10:1727–1738. 2005. View Article : Google Scholar : PubMed/NCBI
27	Montero AJ and Jassem J: Cellular redox pathways as a therapeutic target in the treatment of cancer. Drugs. 71:1385–1396. 2011. View Article : Google Scholar : PubMed/NCBI
28	Solinas G, Marchesi F, Garlanda C, Mantovani A and Allavena P: Inflammation-mediated promotion of invasion and metastasis. Cancer Metastasis Rev. 29:243–248. 2010. View Article : Google Scholar : PubMed/NCBI
29	Maher P: The effects of stress and aging on glutathione metabolism. Ageing Res Rev. 4:288–314. 2005. View Article : Google Scholar : PubMed/NCBI
30	Yuan J, Zhang Z, Li L and Song W: Resveratrol affects the expression of glutamate cysteine ligase in the kidneys of aged rats. Exp Ther Med. 7:1762–1766. 2014.PubMed/NCBI
31	Estrela JM, Ortega A and Obrador E: Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci. 43:143–181. 2006. View Article : Google Scholar
32	Backos DS, Franklin CC and Reigan P: The role of glutathione in brain tumor drug resistance. Biochem Pharmacol. 83:1005–1012. 2012. View Article : Google Scholar : PubMed/NCBI