The subunits of glutamate cysteine ligase enhance cisplatin resistance in human non-small cell lung cancer xenografts in vivo.
The subunits of glutamate cysteine ligase enhance cisplatin resistance in human non-small cell lung cancer xenografts in vivo.
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DOI：
10.3892/ijo.25.2.413
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发表时间：
2004-08
影响因子：
5.2
通讯作者：
S. Fujimori;Y. Abe;M. Nishi;A. Hamamoto;Y. Inoue;Y. Ohnishi;Chiyoko Nishime;H. Matsumoto;H. Yamazaki;H. Kijima;Y. Ueyama;H. Inoue;Masato Nakamura
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作者：
S. Fujimori;Y. Abe;M. Nishi;A. Hamamoto;Y. Inoue;Y. Ohnishi;Chiyoko Nishime;H. Matsumoto;H. Yamazaki;H. Kijima;Y. Ueyama;H. Inoue;Masato Nakamura
谷氨酸半胱氨酸连接酶(GCL)是谷胱甘肽(GSH)合成的关键酶，在抗癌药物尤其是顺铂(CDDP)的细胞内解毒中起重要作用。GCL由修饰剂或轻链亚基(GCLM)和催化或重链亚基(GCLC)组成。目前尚不清楚这些亚单位是否对顺铂耐药至关重要。应用实时定量聚合酶链式反应(PCR)技术，检测了39例人非小细胞肺癌[NSCLC；10例腺癌(Ad)，17例鳞癌(Sq)和12例大细胞癌(La)]移植瘤中GCLM和GCLC基因的表达。用体内药敏试验评价9株异种移植瘤(4株Ad、2株Sq和3株La)对顺铂的敏感性。在每种异种移植物中，GCLM和GCLCmRNA的表达之间存在显著的相关性(Fisher‘s test，p<；0.045)。鳞状细胞癌移植瘤的Gclm基因表达水平显著高于腺癌移植瘤(p=0.023，t检验)，而不同组织病理学移植瘤的Gclc基因表达水平无显著差异。9例异种移植中3例对顺铂敏感(Mann-Whitney U检验，P<；0.01，单侧)，其余6例耐药。GCL亚基共表达与顺铂药物敏感性显著相关(CHI2检验，Yates‘s校正，p=0.014)。这些结果表明，GCL亚基的共表达与体内人NSCLC移植瘤的顺铂耐药有关。
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.