Inhibition of NOTCH3 signalling significantly enhances sensitivity to cisplatin in EBV‐associated nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy which is prevalent in south-east Asia and southern China. Despite the multiple genetic and epigenetic changes reported, the contribution of dysregulated signalling pathways to this distinct type of head and neck cancer is not well understood. Here we demonstrate the up-regulation of NOTCH ligands (JAG1 or DLL4) and effector (HEY1) in the majority of EBV-positive tumour lines and primary tumours. Among the NOTCH receptors, NOTCH3 was over-expressed in all EBV-positive tumour lines and 92.5% of primary tumours. Aberrant activation of NOTCH3 signalling was consistently detected in all these samples. These findings imply that NOTCH3 may play an crucial role in the development of NPC. By NOTCH3 specific siRNA, NOTCH3 signalling was suppressed and thereby significant growth inhibition and apoptosis induction occurred in NPC cells. Down-regulation of a number of targets involved in cell proliferation, eg CCND1, C-MYC,NFKB1, and survival, eg BCL2, BCL-XL, SURVIVIN, was confirmed in the NOTCH3 knockdown NPC cells. Importantly, NOTCH3 knockdown highly enhanced the sensitivity of NPC cells to cisplatin treatment. Furthermore, we revealed that the ability of NPC cells to form spheroids in vitro and tumours in nude mice was also significantly decreased after knockdown of NICD3 expression. These findings indicate that activation of NOTCH3 pathway is a critical oncogenic event in NPC tumourigenesis. Targeting NOTCH3 signalling may serve as a potential therapeutic approach for treating patients suffering from EBV-associated NPC.

Alteration of gene expression and DNA methylation in drug-resistant gastric cancer

“…It has also been reported that expression levels of Notch3 were increased in rat tracheal epithelial cells after treatment with 5-FU (20). NOTCH3 knockdown enhanced the sensitivity of nasopharyngeal carcinoma cells to CDDP treatment (21), and NOTCH3 overexpression correlated with shorter progressionfree/overall survival in patients with advanced stage ovarian carcinoma treated with platinum and taxane (22). In our data, NOTCH3 was upregulated in drug-resistant cells.…”

Notch3 signaling-mediated melanoma–endothelial crosstalk regulates melanoma stem-like cell homeostasis and niche morphogenesis

“…These studies, like ours, underline the contextual complexity of Notch signaling and may inform prospective genotyping or screening criteria for future patient selection. Combinatorial use of Notch-targeted strategies with cytotoxic agents has shown encouraging clinical efficacies in ovarian cancers (54–57) and nasopharyngeal carcinoma (58). Hence, Notch-targeted approaches in combination with conventional or current state-of-the-art pathway-specific targeting strategies poise tremendous potentials as new therapeutic regimens in treating melanoma.…”

VEGFR-3 and CXCR4 as predictive markers for treatment with fluorouracil, leucovorin plus either oxaliplatin or cisplatin in patients with advanced esophagogastric cancer: a comparative study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

“…Tamella and colleagues [9] revealed that VEGFR-3 upregulation in endothelial tip cells, caused by inhibition of the Notch signalling pathway, played a crucial role in sprouting angiogenesis in tumours. Since Notch inhibition has also been connected with the enhanced toxicity of cisplatin in colorectal cancer lines and nasopharyngeal adenocarcinoma [41,42], our results may indicate a similar pathophysiological mechanism for advanced esophagogastric cancer. The reason why oxaliplatin appeared to be less effective in VEGFR-3 positive patients remains unknown.…”