Koucka Kamila, Spalenkova Alzbeta, Seborova Karolina, Tesarova Tereza, Ehrlichova Marie, Krus Ivona, Holy Petr, Rob Lukas, Hruda Martin, Bouda Jiri, Bartakova Alena, Smoligova Vendula, Ojima Iwao, Chen Lei, Bendale Hersch, Mrhalova Marcela, Kopeckova Katerina, Soucek Pavel, Vaclavikova Radka
Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic; Laboratory of Pharmacogenomics, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic.
Biomed Pharmacother. 2025 Oct;191:118532. doi: 10.1016/j.biopha.2025.118532. Epub 2025 Sep 8.
Patients with epithelial ovarian cancer (EOC) face high mortality due to late diagnosis, recurrence, metastasis, and drug resistance. The NOTCH signaling pathway plays a critical role in cancer progression. This study analyzed NOTCH pathway deregulation in EOC patients and its response to taxane treatment in vitro and in vivo. In tumor cells of EOC patients, a significant upregulation of NOTCH1/3/4 and JAG2 and a downregulation of the NOTCH2 gene were found. The observed high levels of NOTCH3 mRNA were also confirmed at the protein level. In contrast, we observed a significant association of low NOTCH4 expression with the presence of peritoneal metastasis and shortened platinum-free interval. In the resistant in vitro cell line model, significant upregulation of NOTCH signaling pathway, namely NOTCH3, was observed after treatment with experimental Stony Brook taxanes (SB-Ts), with high efficacy against paclitaxel-resistant ovarian tumor cells. The administration of SB-Ts also caused NOTCH3 upregulation in an effective combination regimen with paclitaxel in comparison to paclitaxel alone and untreated control in the in vivo cell-derived xenograft mouse model of resistant ovarian cancer. Knockdown of the NOTCH3 gene caused higher sensitivity of resistant cells to taxanes, suggesting that NOTCH3-specific inhibition may potentially bring therapeutic benefits in resistant ovarian carcinoma. Based on our results, we suggest the NOTCH3 gene as a potential target for preclinical studies on resistant ovarian tumors. The current study also highlights the NOTCH4 gene as a potential predictive biomarker of therapeutic response in ovarian cancer.
上皮性卵巢癌（EOC）患者由于诊断延迟、复发、转移和耐药性而面临高死亡率。NOTCH信号通路在癌症进展中起关键作用。本研究分析了EOC患者中NOTCH通路失调及其在体外和体内对紫杉烷治疗的反应。在EOC患者的肿瘤细胞中，发现NOTCH1/3/4和JAG2显著上调，而NOTCH2基因下调。在蛋白质水平也证实了观察到的高水平NOTCH3 mRNA。相反，我们观察到低NOTCH4表达与腹膜转移的存在和无铂间期缩短显著相关。在耐药的体外细胞系模型中，用实验性石溪紫杉烷（SB-Ts）处理后，观察到NOTCH信号通路，即NOTCH3显著上调，其对紫杉醇耐药的卵巢肿瘤细胞具有高效。在耐药卵巢癌的体内细胞源性异种移植小鼠模型中，与单独使用紫杉醇和未处理的对照相比，SB-Ts与紫杉醇联合用药时也导致NOTCH3上调。敲低NOTCH3基因使耐药细胞对紫杉烷更敏感，这表明NOTCH3特异性抑制可能为耐药性卵巢癌带来潜在的治疗益处。基于我们的结果，我们建议将NOTCH3基因作为耐药卵巢肿瘤临床前研究的潜在靶点。本研究还强调NOTCH4基因作为卵巢癌治疗反应的潜在预测生物标志物。
