Molecular impact of NOTCH signaling dysregulation on ovarian cancer progression, chemoresistance, and taxane response

Abstract

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.