奥拉帕尼通过抑制SIRT1刺激卵巢癌细胞衰老

IF 1.7 4区 化学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yanjun Wang, Xi Liu
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引用次数: 0

摘要

目的:诱导卵巢癌细胞衰老已成为一种很有前景的治疗策略。奥拉帕尼是首个获批的PARP抑制剂,广泛用于治疗包括卵巢癌在内的各种癌症。本研究旨在探讨奥拉帕尼对卵巢癌细胞衰老的诱导作用。方法:分别用浓度为15、30、60 μM的奥拉帕尼处理A2780卵巢癌细胞。通过测量8-羟基-2 ' -脱氧鸟苷(8-OHdG)和γ - h2ax水平来评估DNA损伤。采用衰老相关β-半乳糖苷酶(SA-β-Gal)染色和端粒酶活性测定评估细胞衰老。采用real-time PCR和Western blotting分别分析基因和蛋白的表达情况。结果和讨论:奥拉帕尼治疗导致A2780细胞端粒酶活性显著降低。8-OHdG和γ - h2ax水平的增加也证明了它会引起DNA损伤。此外,SA-β-Gal染色阳性证实奥拉帕尼促进细胞衰老。奥拉帕尼治疗导致hTERT和Lamin B1的表达降低,这两者分别是与细胞增殖和核完整性相关的标志物。值得注意的是,奥拉帕尼下调了SIRT1的表达,SIRT1是细胞衰老的关键调节因子,而上调了赖氨酸382 (ac-p53K382)和p21的乙酰化表达。过表达SIRT1可减轻奥拉帕尼诱导的A2780细胞衰老。结论:这些发现揭示了奥拉帕尼通过抑制SIRT1促进卵巢癌细胞衰老的新的药理活性和分子机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Olaparib Stimulates the Senescence of Ovarian Cancer Cells by Inhibiting SIRT1

Olaparib Stimulates the Senescence of Ovarian Cancer Cells by Inhibiting SIRT1

Objective: The induction of cellular senescence in ovarian cancer cells has emerged as a promising therapeutic strategy. Olaparib, the first approved PARP inhibitor, is widely used in the treatment of various cancers, including ovarian cancer. This study aimed to investigate the effects of olaparib on the induction of senescence in ovarian cancer cells. Methods: A2780 ovarian cancer cells were treated with olaparib at concentrations of 15, 30, and 60 μM. DNA damage was assessed by measuring levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and γH2AX. Cellular senescence was evaluated using senescence-associated β-galactosidase (SA-β-Gal) staining and telomerase activity assays. Gene and protein expression were analyzed by real-time PCR and Western blotting, respectively. Results and Discussion: Olaparib treatment led to a significant reduction in telomerase activity in A2780 cells. It also induced DNA damage, as evidenced by increased levels of 8-OHdG and γH2AX. Furthermore, olaparib promoted cellular senescence, confirmed by positive SA-β-Gal staining. Treatment with olaparib resulted in decreased expression of hTERT and Lamin B1, both of which are markers associated with cellular proliferation and nuclear integrity, respectively. Notably, olaparib downregulated the expression of SIRT1, a key regulator of cellular senescence, while upregulating acetylation of p53 at lysine 382 (ac-p53K382) and p21 expression. Overexpression of SIRT1 attenuated olaparib-induced senescence in A2780 cells. Conclusions: These findings reveal a novel pharmacological activity and molecular mechanism of olaparib in promoting senescence in ovarian cancer cells through SIRT1 inhibition.

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来源期刊
Russian Journal of Bioorganic Chemistry
Russian Journal of Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
1.80
自引率
10.00%
发文量
118
审稿时长
3 months
期刊介绍: Russian Journal of Bioorganic Chemistry publishes reviews and original experimental and theoretical studies on the structure, function, structure–activity relationships, and synthesis of biopolymers, such as proteins, nucleic acids, polysaccharides, mixed biopolymers, and their complexes, and low-molecular-weight biologically active compounds (peptides, sugars, lipids, antibiotics, etc.). The journal also covers selected aspects of neuro- and immunochemistry, biotechnology, and ecology.
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