Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, Jiangsu 221002, China.
Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, Jiangsu 221002, China.
Cancer Lett. 2015 Mar 1;358(1):8-16. doi: 10.1016/j.canlet.2014.12.038. Epub 2014 Dec 17.
Genomic stability depends on an efficient DNA damage repair system to keep the chromosomes intact. Unrepaired DNA damage not only causes cell cycle arrest, apoptosis, but also accumulates genome mutations. DNA damage response (DDR) exhibits a critical function on the protection against human cancer, as indicated by the high predisposition to cancer of individuals with germ-line mutations in DDR genes. However, a defective DNA repair is liked intimately with the unchecked proliferation and the intrinsic resistance to clinical DNA-damaging agents. Therefore, abrogation of specific proteins in DNA damage repair pathways is a promising strategy for developing targeted cancer treatments. It may sound paradoxical to inhibit DDR pathway for sensitization of clinical therapy because cancer promotion and malignant transformation are aided by deficient DNA repair pathways. Actually, DDR acts as a positive guardian of genomic stability to prevent from tumorigenesis. On the other hand, DDR also performs as a negative saboteur to resist chemo- and radiotherapy. In this regard, DDR functions as "a double-edged sword" in cancer prevention and cancer therapy. The defective DDR that makes cancer cells of high mutability should alternatively provide therapeutic opportunities that confer the lethality to cancer cells without harming normal cells.
基因组稳定性依赖于高效的 DNA 损伤修复系统以保持染色体的完整性。未修复的 DNA 损伤不仅会导致细胞周期停滞、细胞凋亡，还会导致基因组突变的积累。DNA 损伤反应 (DDR) 在预防人类癌症方面具有重要作用，这一点可以从 DDR 基因种系突变个体癌症易感性高这一事实得到证实。然而，有缺陷的 DNA 修复与不受控制的增殖和对临床 DNA 损伤药物的内在耐药性密切相关。因此，在 DNA 损伤修复途径中特异性蛋白的缺失可能是开发靶向癌症治疗的一种很有前途的策略。这听起来可能有些矛盾，因为 DDR 途径的抑制会使临床治疗变得敏感，因为癌症的促进和恶性转化是由 DNA 修复途径的缺陷所辅助的。实际上，DDR 作为基因组稳定性的积极守护者，可防止肿瘤发生。另一方面，DDR 还可作为一种负面破坏者来抵抗化疗和放疗。在这方面，DDR 在癌症预防和癌症治疗中充当了一把双刃剑。有缺陷的 DDR 会使癌细胞具有高突变性，反而为赋予癌细胞致死性而不伤害正常细胞提供了治疗机会。
