Cheng Shu-Yuan, Seo Jiwon, Huang Bik Tzu, Napolitano Tanya, Champeil Elise
Department of Sciences, John Jay College of Criminal Justice, City University of New York, NY 10019, USA.
Int J Oncol. 2016 Nov;49(5):1815-1824. doi: 10.3892/ijo.2016.3703. Epub 2016 Sep 23.
Mitomycin C (MC), a commonly used anticancer drug, induces DNA damage via DNA alkylation. Decarbamoyl mitomycin C (DMC), another mitomycin lacking the carbamate at C10, generates similar lesions as MC. Interstrand cross-links (ICLs) are believed to be the lesions primarily responsible for the cytotoxicity of MC and DMC. The major ICL generated by MC (α-ICL) has a trans stereochemistry at the guanine-drug linkage whereas the major ICL from DMC (β-ICL) has the opposite, cis, stereochemistry. In addition, DMC can provoke strong p53-independent cell death. Our hypothesis is that the stereochemistry of the major unique β-ICL generated by DMC is responsible for this p53-independent cell death signaling. p53 gene is inactively mutated in more than half of human cancers. p21WAF1/CIP1 known as a major effector of p53 is involved in p53-dependent and -independent control of cell proliferation and death. This study revealed the role of p21WAF1/CIP1 on MC and DMC triggered cell damage. MCF-7 (p53-proficient) and K562 (p53-deficient) cells were used. Cell cycle distributions were shifted to the G1/S phase in MCF-7 treated with MC and DMC, but were shifted to the S phase in K562. p21WAF1/CIP1 activation was observed in both cells treated with MC and DMC, and DMC triggered more significant activation. Knocking down p53 in MCF-7 did not attenuate MC and DMC induced p21WAF1/CIP1 activation. The α-ICL itself was enough to cause p21WAF1/CIP1 activation.
丝裂霉素C（MC）是一种常用的抗癌药物，通过DNA烷基化诱导DNA损伤。去氨甲酰丝裂霉素C（DMC）是另一种在C10位缺乏氨基甲酸酯的丝裂霉素，产生与MC类似的损伤。链间交联（ICL）被认为是主要导致MC和DMC细胞毒性的损伤。MC产生的主要ICL（α-ICL）在鸟嘌呤-药物连接处以反式立体化学存在，而DMC产生的主要ICL（β-ICL）具有相反的顺式立体化学。此外，DMC可引发强烈的p53非依赖性细胞死亡。我们的假设是，DMC产生的主要独特β-ICL的立体化学负责这种p53非依赖性细胞死亡信号传导。p53基因在超过一半的人类癌症中发生失活突变。p21WAF1/CIP1作为p53的主要效应因子，参与p53依赖性和非依赖性的细胞增殖和死亡控制。本研究揭示了p21WAF1/CIP1在MC和DMC引发的细胞损伤中的作用。使用了MCF-7（p53功能正常）和K562（p53缺陷）细胞。用MC和DMC处理的MCF-7细胞的细胞周期分布向G1/S期转变，但用MC和DMC处理的K562细胞的细胞周期分布向S期转变。在用MC和DMC处理的两种细胞中均观察到p21WAF1/CIP1激活，且DMC引发更显著的激活。在MCF-7中敲低p53并没有减弱MC和DMC诱导的p21WAF1/CIP1激活。α-ICL本身就足以引起p21WAF1/CIP1激活。
