Glaviano Antonino, Singh Samarendra K, Lee E Hui Clarissa, Okina Elena, Lam Hiu Yan, Carbone Daniela, Reddy E Premkumar, O'Connor Mark J, Koff Andrew, Singh Garima, Stebbing Justin, Sethi Gautam, Crasta Karen Carmelina, Diana Patrizia, Keyomarsi Khandan, Yaffe Michael B, Wander Seth A, Bardia Aditya, Kumar Alan Prem
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
School of Biotechnology, Institute of Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Pharmacol Rev. 2025 Mar;77(2):100030. doi: 10.1016/j.pharmr.2024.100030. Epub 2024 Dec 24.
Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated cell growth. Genetic mutations can determine tumor onset by either augmenting cell division rates or restraining normal controls such as cell cycle arrest or apoptosis. As a result, tumor cells not only undergo uncontrolled cell division but also become compromised in their ability to exit the cell cycle accurately. Regulation of cell cycle progression is enabled by specific surveillance mechanisms known as cell cycle checkpoints, and aberrations in these signaling pathways often culminate in cancer. For instance, DNA damage checkpoints, which preclude the generation and augmentation of DNA damage in the G1, S, and G2 cell cycle phases, are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Notably, tumors have evolved to become dependent on checkpoints for their survival. For example, checkpoint pathways such as the DNA replication stress checkpoint and the mitotic checkpoint rarely undergo mutations and remain intact because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation leading to cell death. In this review, we initially focus on cell cycle control pathways and specific functions of checkpoint signaling involved in normal and cancer cells and then proceed to examine how cell cycle control and checkpoint mechanisms can provide new therapeutic windows that can be exploited for cancer therapy. SIGNIFICANCE STATEMENT: DNA damage checkpoints are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Conversely, DNA replication stress and mitotic checkpoints rarely undergo mutations because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation, leading to cancer cell death. This review focuses on the checkpoint signaling mechanisms involved in cancer cells and how an emerging understanding of these pathways can provide new therapeutic opportunities for cancer therapy.
癌症是细胞周期活动异常和细胞生长失调的全身性表现。基因突变可通过提高细胞分裂速率或抑制诸如细胞周期停滞或凋亡等正常调控机制来决定肿瘤的发生。因此，肿瘤细胞不仅经历不受控制的细胞分裂，而且其准确退出细胞周期的能力也受到损害。细胞周期进程的调控是由称为细胞周期检查点的特定监测机制实现的，这些信号通路的异常往往最终导致癌症。例如，DNA损伤检查点可防止在G1、S和G2细胞周期阶段产生和增加DNA损伤，癌细胞中的这些检查点常常存在缺陷，使得细胞尽管积累了遗传错误仍能进行分裂。值得注意的是，肿瘤已经进化到依赖检查点来维持生存。例如，诸如DNA复制应激检查点和有丝分裂检查点等检查点通路很少发生突变并保持完整，因为任何异常活动都可能导致无法修复的损伤或灾难性的染色体错配，从而导致细胞死亡。在本综述中，我们首先关注正常细胞和癌细胞中涉及的细胞周期控制通路以及检查点信号的特定功能，然后着手研究细胞周期控制和检查点机制如何能够提供可用于癌症治疗的新治疗窗口。重要声明：DNA损伤检查点在癌细胞中常常存在缺陷，使得细胞尽管积累了遗传错误仍能进行分裂。相反，DNA复制应激和有丝分裂检查点很少发生突变，因为任何异常活动都可能导致无法修复的损伤或灾难性的染色体错配，从而导致癌细胞死亡。本综述聚焦于癌细胞中涉及的检查点信号机制，以及对这些通路的新认识如何能够为癌症治疗提供新的治疗机会。
