The subunits of glutamate cysteine ligase enhance cisplatin resistance in human non-small cell lung cancer xenografts in vivo.
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.
Fujimori
Sakashi
S
Department of General Thoracic Surgery, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan.
Abe
Yoshiyuki
Y
Nishi
Masatake
M
Hamamoto
Atsushi
A
Inoue
Yoshimasa
Y
Ohnishi
Yasuyuki
Y
Nishime
Chiyoko
C
Matsumoto
Hozumi
H
Yamazaki
Hitoshi
H
Kijima
Hiroshi
H
Ueyama
Yoshito
Y
Inoue
Hiroshi
H
Nakamura
Masato
M
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis / Q000378:metabolism; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D021122:Protein Subunits; D012334:RNA, Neoplasm; D005721:Glutamate-Cysteine Ligase; D002945:Cisplatin