Department of Pharmacy, University Bonn, 53121 Bonn, Germany.
Institute of Medical Virology, University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany; Interdisciplinary Laboratory for Paediatric Tumour and Virus Research, Dr. Petra Joh Research Institute, 60528 Frankfurt am Main, Germany.
Biochim Biophys Acta Mol Basis Dis. 2024 Dec;1870(8):167448. doi: 10.1016/j.bbadis.2024.167448. Epub 2024 Aug 6.
The levels and activities of the DNA/RNA helicase schlafen11 (SLFN11) and the serine/threonine-protein kinase ataxia telangiectasia and Rad3-related protein (ATR) may determine cancer cell sensitivity to DNA damaging agents, including platinum drugs. Here, we studied the roles of SLFN11 and ATR in cisplatin resistance of ovarian cancer using cell lines displaying acquired or intrinsic cisplatin resistance. W1CR, the cisplatin-resistant subline of W1 ovarian cancer cells, displayed reduced SLFN11 levels. HDAC inhibition using entinostat returned an epigenetic downregulation of SLFN11 in W1CR cells, caused SLFN11 re-expression and re-sensitized these cells to cisplatin. Moreover, entinostat also sensitized intrinsically resistant EFO21 ovarian cancer cells to cisplatin by upregulating SLFN11. However, SLFN11 was not involved in cisplatin resistance in all other cell models. Thus, SLFN11 expression is not a general cisplatin resistance marker in ovarian cancer. In contrast, inhibition of the DNA damage repair master regulator ATR using sub-toxic concentrations of elimusertib sensitized parental cell lines as well as intrinsically resistant EFO21 cells to cisplatin, and fully reversed acquired cisplatin resistance in cisplatin-adapted sublines W1CR, A2780cis, and KuramochiCDDP. Mechanisms underlying ATR-mediated cisplatin resistance differed between the cell lines and included CHK1/WEE1 signaling and induction of homologous recombination. In conclusion, SLFN11 and ATR are involved in ovarian cancer cisplatin resistance. Although our data identify ATR as key target for tackling cisplatin resistance in ovarian cancer, future studies are needed to identify biomarkers that indicate, which individual ovarian cancers benefit from SLFN11 re-activation and/or ATR inhibition.
DNA/RNA 解旋酶 Schlafen11（SLFN11）和丝氨酸/苏氨酸蛋白激酶共济失调毛细血管扩张症和 Rad3 相关蛋白（ATR）的水平和活性可能决定癌细胞对包括铂类药物在内的 DNA 损伤剂的敏感性。在这里，我们使用显示获得性或内在顺铂耐药的细胞系研究了 SLFN11 和 ATR 在卵巢癌顺铂耐药中的作用。W1CR 是 W1 卵巢癌细胞的顺铂耐药亚系，其 SLFN11 水平降低。使用恩替诺特抑制 HDAC 会导致 W1CR 细胞中 SLFN11 的表观遗传下调，引起 SLFN11 重新表达，并使这些细胞对顺铂重新敏感。此外，恩替诺特还通过上调 SLFN11 使内在耐药的 EFO21 卵巢癌细胞对顺铂敏感。然而，SLFN11 并不参与所有其他细胞模型中的顺铂耐药。因此，SLFN11 表达不是卵巢癌中普遍的顺铂耐药标志物。相比之下，使用低毒性浓度的 elimusertib 抑制 DNA 损伤修复主调节剂 ATR 可使亲本细胞系以及内在耐药的 EFO21 细胞对顺铂敏感，并完全逆转顺铂适应的亚系 W1CR、A2780cis 和 KuramochiCDDP 中的获得性顺铂耐药。ATR 介导的顺铂耐药的机制在细胞系之间有所不同，包括 CHK1/WEE1 信号传导和同源重组的诱导。总之，SLFN11 和 ATR 参与了卵巢癌的顺铂耐药。尽管我们的数据将 ATR 鉴定为克服卵巢癌顺铂耐药的关键靶标，但仍需要进一步的研究来确定哪些个体卵巢癌受益于 SLFN11 重新激活和/或 ATR 抑制的生物标志物。
