An overactive neddylation pathway serves as a therapeutic target and MLN4924 enhances the anticancer activity of cisplatin in pancreatic cancer

Abstract

The survival rate of patients with pancreatic cancer is between 3 and 5%. The neddylation pathway is overactive in multiple cancer types and is associated with poor prognosis. In recent years, the neddylation process has become a popular research target for the development of novel cancer therapies. However, the activation level of the pathway, and whether its targeting sensitizes pancreatic cancer cells to cisplatin treatment is currently unclear. In the present study, using reverse transcription-quantitative PCR and western blot analyses, the neddylation pathway was observed to be overactivated at the protein, but not the mRNA level. In addition, by analyzing The Cancer Genome Atlas data, it was demonstrated that high expression levels of NEDD8 activating enzyme E1 subunit 1 were observed to be a predictor of poor prognosis for patients with pancreatic cancer. Cisplatin enhanced the cytotoxic effects of MLN4924 both in vitro and in vivo according to Cell Counting kit-8 assays and an in vivo tumor model. Further mechanistic studies, including western blotting and immunohistochemistry assays, revealed that combined MLN4924 and cisplatin treatment induced higher levels of DNA damage by increasing the accumulation of well-defined cullin-ring ligase substrates, such as chromatin licensing and DNA replication factor 1, origin recognition complex subunit 1, p21, p27 and phosphorylated IκBα. The results of the present study support the clinical use of combined neddylation inhibitor and cisplatin treatment, which may improve the survival of, and impart other benefits for patients with pancreatic cancer.

MLN4924 inhibits cell proliferation by targeting the activated neddylation pathway in endometrial carcinoma

“… 20 The neddylation pathway is reported to be overactivated in multiple cancer types, including liver, lung and colon cancer, and its overactivation indicates poor prognosis. 23 In the present study, the expression profiles of key neddylation genes were analysed in TCGA samples using an online server.…”

Ubiquitin and ubiquitin-like molecules in DNA double strand break repair

“…A deep understanding of the principle and mechanism of these posttranslational modifications can also potentially provide new therapeutics for the cancer patients. The inhibitor of Neddylation E1 enzyme NAE-MLN4924 has been developed and displays dramatic inhibition of hematological malignancies and solid tumors [150][151][152][153][154][155][156][157][158][159][160][161]. Multiple Phase I clinical study of MLN4924 are undergoing [162][163][164][165][166].…”

The Many Potential Fates of Non-Canonical Protein Substrates Subject to NEDDylation

“…A primary disease for consideration would be cancer where dysregulated biochemical pathways are commonly detected. Increased NEDD8 levels along with increased levels of enzymes in the NEDD8 activation and conjugation pathway such as NAE1 have been detected in numerous cancer types, such as pancreatic cancer [103], osteosarcoma [104], bladder [105], and colorectal cancers [106] to name but a few. Interestingly, in the case of colorectal cancers, a non-canonical target of NEDD8 was identified [106].…”