Wang Ziwen, Huang Yujung, Zhang Jiqiang
Department of Preventive Medicine, College of Military Preventive Medicine, Third Military Medical University, Chongqing, 400038, China,
Cell Mol Biol Lett. 2014 Jun;19(2):233-42. doi: 10.2478/s11658-014-0191-7. Epub 2014 Apr 11.
Radiotherapy and chemotherapeutic agents that damage DNA are the current major non-surgical means of treating cancer. However, many patients develop resistances to chemotherapy drugs in their later lives. The PI3K and Ras signaling pathways are deregulated in most cancers, so molecularly targeting PI3K-Akt or Ras-MAPK signaling sensitizes many cancer types to radiotherapy and chemotherapy, but the underlying molecular mechanisms have yet to be determined. During the multi-step processes of tumorigenesis, cancer cells gain the capability to disrupt the cell cycle checkpoint and increase the activity of CDK4/6 by disrupting the PI3K, Ras, p53, and Rb signaling circuits. Recent advances have demonstrated that PI3K-Akt-mTOR signaling controls FANCD2 and ribonucleotide reductase (RNR). FANCD2 plays an important role in the resistance of cells to DNA damage agents and the activation of DNA damage checkpoints, while RNR is critical for the completion of DNA replication and repair in response to DNA damage and replication stress. Regulation of FANCD2 and RNR suggests that cancer cells depend on PI3K-Akt-mTOR signaling for survival in response to DNA damage, indicating that the PI3K-AktmTOR pathway promotes resistance to chemotherapy and radiotherapy by enhancing DNA damage repair.
破坏DNA的放疗和化疗药物是目前治疗癌症的主要非手术手段。然而，许多患者在后期会对化疗药物产生耐药性。PI3K和Ras信号通路在大多数癌症中失调，因此分子靶向PI3K-Akt或Ras-MAPK信号可使多种癌症类型对放疗和化疗敏感，但潜在的分子机制尚未确定。在肿瘤发生的多步骤过程中，癌细胞获得了破坏细胞周期检查点的能力，并通过破坏PI3K、Ras、p53和Rb信号通路来增加CDK4/6的活性。最近的进展表明，PI3K-Akt-mTOR信号控制FANCD2和核糖核苷酸还原酶（RNR）。FANCD2在细胞对DNA损伤剂的抗性和DNA损伤检查点的激活中起重要作用，而RNR对于响应DNA损伤和复制应激完成DNA复制和修复至关重要。对FANCD2和RNR的调节表明，癌细胞在响应DNA损伤时依赖PI3K-Akt-mTOR信号来存活，这表明PI3K-Akt-mTOR通路通过增强DNA损伤修复来促进对化疗和放疗的抗性。
