Pigg Hannah C, Alley Katelyn R, Griffin Christopher R, Moon Caleb H, Kraske Sarah J, DeRose Victoria J
Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon, USA.
Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon, USA.
J Biol Chem. 2024 Nov;300(11):107858. doi: 10.1016/j.jbc.2024.107858. Epub 2024 Oct 5.
The mechanisms of action for the platinum compounds cisplatin and oxaliplatin have yet to be fully elucidated, despite the worldwide use of these drugs. Recent studies suggest that the two compounds may be working through different mechanisms, with cisplatin inducing cell death via the DNA damage response (DDR) and oxaliplatin utilizing a nucleolar stress-based cell death pathway. While cisplatin-induced DDR has been subject to much research, the mechanisms for oxaliplatin's influence on the nucleolus are not well understood. Prior work has outlined structural parameters for Pt(II) derivatives capable of nucleolar stress induction. In this work, we gain insight into the nucleolar stress response induced by these Pt(II) derivatives by investigating potential correlations between this unique pathway and DDR. Key findings from this study indicate that Pt(II)-induced nucleolar stress occurs when DDR is inhibited and works independently of the ATM/ATR-dependent DDR pathway. We also determine that Pt(II)-induced stress may be linked to the G cell cycle phase, as cisplatin can induce nucleolar stress when cell cycle inhibition occurs at the G/S checkpoint. Finally, we compare Pt(II)-induced nucleolar stress with other small-molecule nucleolar stress-inducing compounds Actinomycin D, BMH-21, and CX-5461 and find that Pt(II) compounds cause irreversible nucleolar stress, whereas the reversibility of nucleolar stress induced by small-molecules varies. Taken together, these findings contribute to a better understanding of Pt(II)-induced nucleolar stress, its deviation from ATM/ATR-dependent DDR, and the possible influence of cell cycle on the ability of Pt(II) compounds to cause nucleolar stress.
尽管顺铂和奥沙利铂这两种铂类化合物在全球范围内广泛使用，但其作用机制尚未完全阐明。最近的研究表明，这两种化合物可能通过不同的机制发挥作用，顺铂通过DNA损伤反应（DDR）诱导细胞死亡，而奥沙利铂则利用基于核仁应激的细胞死亡途径。虽然顺铂诱导的DDR已经得到了很多研究，但奥沙利铂对核仁影响的机制尚不清楚。先前的工作已经概述了能够诱导核仁应激的Pt(II)衍生物的结构参数。在这项工作中，我们通过研究这种独特途径与DDR之间的潜在相关性，深入了解了这些Pt(II)衍生物诱导的核仁应激反应。这项研究的主要发现表明，当DDR受到抑制时，Pt(II)诱导的核仁应激就会发生，并且其作用独立于ATM/ATR依赖的DDR途径。我们还确定，Pt(II)诱导的应激可能与G细胞周期阶段有关，因为当细胞周期在G/S检查点受到抑制时，顺铂可以诱导核仁应激。最后，我们将Pt(II)诱导的核仁应激与其他小分子核仁应激诱导化合物放线菌素D、BMH-21和CX-5461进行了比较，发现Pt(II)化合物会导致不可逆的核仁应激，而小分子诱导的核仁应激的可逆性则有所不同。综上所述，这些发现有助于更好地理解Pt(II)诱导的核仁应激、其与ATM/ATR依赖的DDR的偏差以及细胞周期对Pt(II)化合物引起核仁应激能力的可能影响。
