Abstract
BackgroundThe neddylation pathway is aberrantly overactivated in multiple human cancers and has been indicated as an effective target for anticancer therapy in clinical trials. We aimed to study whether the neddylation pathway is upregulated in pancreatic cancer and whether pevonedistat, a first-in-class anticancer agent specifically targeting this pathway, will suppress cancer tumorigenesis and progression.MethodsWe evaluated the expression pattern of neddylation pathway components in 179 pancreatic adenocarcinoma (PAAD) compared with 171 normal tissues from The Cancer Genome Atlas (TCGA) dataset and further assessed PAAD patient prognosis with high neddylation pathway expression via Gene Expression Profiling Interactive Analysis (GEPIA). We then analyzed malignant cancer phenotypes both in vitro and in vivo, as well as intrinsic molecular mechanisms upon pevonedistat treatment.ResultsWe found that the neddylation pathway was hyperactivated in pancreatic cancer. Patients with high neddylation pathway expression exhibited worse prognoses. Pevonedistat significantly inhibited the cancer cell cycle, cell growth, and proliferation; increased cell apoptosis; and decreased cancer cell xenografts in a mouse model. Mechanistically, pevonedistat treatment and the siRNA knockdown neddylation pathway were able to remarkably induce the accumulation of Wee1, p27, and p21. Further mechanistic studies revealed that pevonedistat mainly impaired the ubiquitination level and delayed the protein degradation of Wee1, p27, and p21.ConclusionsOur results showed that pevonedistat targeted the overexpression of the neddylation pathway in pancreatic cancer to induce cell growth suppression by inducing the accumulation of the cell cycle regulators Wee1, p27, and p21, which provides sound evidence for the clinical trial of pevonedistat for pancreatic cancer therapy.
Highlights
The neddylation pathway is aberrantly overactivated in multiple human cancers and has been indicated as an effective target for anticancer therapy in clinical trials
Correlation analysis revealed that the mRNA levels of neural precursor cell expressed developmentally downregulated 8 (NEDD8) and NEDD8-activating enzyme E1 (NAE1), Ubc12, and Rbx1 had a statistically significant association with pancreatic cancer (Figure 1B)
Having shown the upregulated profiles of neddylation pathway members in pancreatic cancer, we evaluated the effects of downregulation of the neddylation pathway on the malignant phenotypes of Miapaca-2 and Capan-1 cells treated with pevonedistat
Summary
The neddylation pathway is aberrantly overactivated in multiple human cancers and has been indicated as an effective target for anticancer therapy in clinical trials. The 5-year survival rate for localized pancreatic cancer is only 39%; for the regional stage, it is 13%; for the distant stage, it is 3%; and for all stages combined, it is 10% [1]. Despite improvements in recent therapeutic strategies and approaches [4, 5], little improvement has been achieved in the survival rate in pancreatic cancer because of drug insensitiveness and tolerance, drug resistance after treatment, severe adverse effects upon treatment, and relatively low efficacy for pancreatic cancer therapy [6], resulting in a high rate of local recurrences, an increased risk of distant metastases, and poor prognosis in pancreatic cancer patients [7]. Independent and personalized anticancer targets are urgently needed to improve the anticancer efficacy of pancreatic cancer and allow better-guided clinical decision-making
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