Tomicic Maja T, Krämer Franziska, Nguyen Alexandra, Schwarzenbach Christian, Christmann Markus
Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
Cancers (Basel). 2021 Apr 22;13(9):2019. doi: 10.3390/cancers13092019.
Senescence is an important consequence of cytostatic drug-based tumor therapy. Here we analyzed to which degree the anticancer drug oxaliplatin induces cell death, cell cycle arrest, and senescence in colorectal cancer (CRC) cells and elucidated the role of p53. Oxaliplatin treatment resulted in the G2-phase arrest in all CRC lines tested (HCT116, HCT116, LoVo, SW48 and SW480). Immunoblot analysis showed that within the p53-competent lines p53 and p21 are activated at early times upon oxaliplatin treatment. However, at later times, only LoVo cells showed sustained activation of the p53/p21 pathway, accompanied by a strong induction of senescence as measured by senescence-associated β-Gal staining and induction of senescence-associated secretory phenotype (SASP) factors. Opposite to LoVo, the p53/p21 response and senescence induction was much weaker in the p53-proficient SW48 and SW480 cells, which was due to deficiency for p14. Thus, among lines studied only LoVo express p14 protein and siRNA-mediated knockdown of p14 significantly reduced sustained p53/p21 activation and senescence. , ectopic p14 expression enhanced oxaliplatin-induced senescence in SW48 and SW480 cells. Our data show that oxaliplatin-induced senescence in CRC cells is dependent on p53 proficiency; however, a significant induction can only be observed upon p14-mediated p53 stabilization.
衰老 是基于细胞抑制药物的肿瘤治疗的一个重要后果。在此，我们分析了抗癌药物奥沙利铂在多大程度上诱导结直肠癌（CRC）细胞发生细胞死亡、细胞周期停滞和衰老，并阐明了p53的作用。奥沙利铂处理导致所有测试的CRC细胞系（HCT116、LoVo、SW48和SW480）出现G2期停滞。免疫印迹分析表明，在具有p53功能的细胞系中，奥沙利铂处理后早期p53和p21被激活。然而，在后期，只有LoVo细胞显示p53/p21途径持续激活，同时通过衰老相关β-半乳糖苷酶染色和衰老相关分泌表型（SASP）因子的诱导来衡量，衰老被强烈诱导。与LoVo相反，在p53功能正常的SW48和SW480细胞中，p53/p21反应和衰老诱导要弱得多，这是由于p14缺乏所致。因此，在所研究的细胞系中，只有LoVo表达p14蛋白，siRNA介导的p14敲低显著降低了p53/p21的持续激活和衰老。此外，异位p14表达增强了SW48和SW480细胞中奥沙利铂诱导的衰老。我们的数据表明，奥沙利铂诱导的CRC细胞衰老依赖于p53功能；然而，只有在p14介导的p53稳定化后才能观察到显著的诱导。
