The subunits of glutamate cysteine ligase enhance cisplatin resistance in human non-small cell lung cancer xenografts in vivo

Int J Oncol. 2004 Aug;25(2):413-8.


Glutamate cysteine ligase (GCL) is a key enzyme in glutathione (GSH) synthesis, and is thought to play a significant role in the intracellular detoxification of anticancer drugs, especially of cisplatin (CDDP). GCL is composed of a modifier or light chain subunit (GCLM) and a catalytic or heavy chain subunit (GCLC). It was unclear whether the subunits are essential to CDDP-resistance. We examined the gene expression of GCLM and GCLC in 39 xenografts of human non-small cell lung cancer [NSCLC; 10 adenocarcinoma (Ad), 17 squamous cell carcinoma (Sq) and 12 large cell carcinoma (La)] by real-time polymerase chain reaction (PCR) with human-specific primers. Drug sensitivity to CDDP was evaluated in the 9 xenografts (4 Ad, 2 Sq and 3 La) using an in vivo drug sensitivity test. There was a significant association between the expression of GCLM and GCLC mRNA in each xenograft (Fisher's test, p<0.045). Squamous cell carcinoma xenografts significantly showed higher expression of GCLM gene than adenocarcinoma xenografts (p=0.023, t-test), while there was no significant difference in GCLC gene expression levels between each histopathological xenograft. Three of nine xenografts were sensitive to CDDP (Mann-Whitney U test, p<0.01, one-sided), while the other 6 xenografts were resistant. There was a significant relationship between drug sensitivity to CDDP and the co-overexpression of GCL subunits (chi2 test for independence, Yates' correction, p=0.014). These results suggested that the co-overexpression of GCL subunits correlated with CDDP-resistance in human NSCLC xenograft in vivo.

MeSH terms

  • Animals
  • Antineoplastic Agents / antagonists & inhibitors*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Cisplatin / antagonists & inhibitors*
  • Cisplatin / therapeutic use
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Mice
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • RNA, Neoplasm / analysis
  • RNA, Neoplasm / metabolism
  • Transplantation, Heterologous
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Protein Subunits
  • RNA, Neoplasm
  • Glutamate-Cysteine Ligase
  • Cisplatin