Chang Dong Kyung, Goel Ajay, Ricciardiello Luigi, Lee Dong Ho, Chang Christina L, Carethers John M, Boland C Richard
Department of Medicine and Comprehensive Cancer Center, University of California San Diego, 4028 Basic Science Building, 9500 Gilman Drive, La Jolla 92093-0688, USA.
Cancer Lett. 2003 Jun 10;195(2):243-51. doi: 10.1016/s0304-3835(03)00145-9.
Patients who develop tumors with Lynch syndrome, which is caused by mutational inactivation of the DNA mismatch repair (MMR) system, have a relatively favorable prognosis compared to patients who develop sporadic tumors. Paradoxically, DNA MMR-deficient cells are resistant to many chemotherapeutic agents, and are capable of bypassing the G2/M checkpoint in vitro. Colon cancers that develop in the setting of Lynch syndrome show an abundant recruitment of immune cells into tumor tissues, which might be expected to increase oxyradical formation, and make the tumor cells more vulnerable to cell death. We examined the chemosensitivity and cell cycle response to oxidative stress in several MMR-deficient (HCT116, SW48, and DLD1) and -proficient (CaCo2, SW480, and HT29) colorectal cancer cell lines. H(2)O(2) induced a G2/M cell cycle arrest in both MMR deficient and proficient cell lines, however MMR-deficient cell lines were more sensitive to H(2)O(2) toxicity, and the response was more prolonged in MMR-deficient cells. Interestingly, human MutL-homologue (hMLH1-)defective HCT116 and hMLH1-restored HCT116+ch3 cell lines responded to H(2)O(2) with the same degree of G2/M arrest. The survival response of HCT116+ch3 was nearly identical to that of hMLH1-defective HCT116+ch2, although better than the response observed in HCT116 cells. In conclusion, greater cellular sensitivity and G2/M arrest in response to oxidative stress in MMR-deficient colorectal cancer cells could be one of the reasons for the more favorable prognosis seen in patients with Lynch syndrome. However, this sensitivity appears not to be a direct result of a deficient MMR function, but is more likely attributable to spectrum of target gene mutations that occurs in MMR-deficient tumors.
因DNA错配修复（MMR）系统突变失活而患林奇综合征相关肿瘤的患者，与患散发性肿瘤的患者相比，预后相对较好。矛盾的是，DNA错配修复缺陷的细胞对许多化疗药物具有抗性，并且在体外能够绕过G2/M期检验点。在林奇综合征背景下发生的结肠癌显示免疫细胞大量募集到肿瘤组织中，这可能会增加氧自由基的形成，并使肿瘤细胞更容易发生细胞死亡。我们检测了几种错配修复缺陷（HCT116、SW48和DLD1）及错配修复功能正常（CaCo2、SW480和HT29）的结肠癌细胞系对化疗的敏感性以及细胞周期对氧化应激的反应。H2O2在错配修复缺陷和功能正常的细胞系中均诱导G2/M期细胞周期停滞，然而错配修复缺陷的细胞系对H2O2毒性更敏感，并且在错配修复缺陷的细胞中反应持续时间更长。有趣的是，人MutL同源物（hMLH1）缺陷的HCT116细胞系和hMLH1恢复的HCT116+ch3细胞系对H2O2的反应表现出相同程度的G2/M期停滞。HCT116+ch3的存活反应与hMLH1缺陷的HCT116+ch2几乎相同，尽管优于在HCT116细胞中观察到的反应。总之，错配修复缺陷的结肠癌细胞对氧化应激具有更高的细胞敏感性和G2/M期停滞，这可能是林奇综合征患者预后较好的原因之一。然而，这种敏感性似乎不是错配修复功能缺陷的直接结果，而更可能归因于错配修复缺陷肿瘤中发生的靶基因突变谱。
