Frontiers in Oncology (Jan 2022)
Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation Pathway
- Junfeng Xu,
- Junfeng Xu,
- Junfeng Xu,
- Junfeng Xu,
- Zheng Li,
- Zheng Li,
- Zheng Li,
- Zheng Li,
- Qifeng Zhuo,
- Qifeng Zhuo,
- Qifeng Zhuo,
- Qifeng Zhuo,
- Zeng Ye,
- Zeng Ye,
- Zeng Ye,
- Zeng Ye,
- Guixiong Fan,
- Guixiong Fan,
- Guixiong Fan,
- Guixiong Fan,
- Heli Gao,
- Heli Gao,
- Heli Gao,
- Heli Gao,
- Shunrong Ji,
- Shunrong Ji,
- Shunrong Ji,
- Shunrong Ji,
- Xianjun Yu,
- Xianjun Yu,
- Xianjun Yu,
- Xianjun Yu,
- Xiaowu Xu,
- Xiaowu Xu,
- Xiaowu Xu,
- Xiaowu Xu,
- Wensheng Liu,
- Wensheng Liu,
- Wensheng Liu,
- Wensheng Liu,
- Wenyan Xu,
- Wenyan Xu,
- Wenyan Xu,
- Wenyan Xu
Affiliations
- Junfeng Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Junfeng Xu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Junfeng Xu
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Junfeng Xu
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Zheng Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Zheng Li
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Zheng Li
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Zheng Li
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Qifeng Zhuo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Qifeng Zhuo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Qifeng Zhuo
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Qifeng Zhuo
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Zeng Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Zeng Ye
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Zeng Ye
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Zeng Ye
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Guixiong Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Guixiong Fan
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Guixiong Fan
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Guixiong Fan
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Heli Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Heli Gao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Heli Gao
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Heli Gao
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Shunrong Ji
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shunrong Ji
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Shunrong Ji
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Xianjun Yu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Xianjun Yu
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Xianjun Yu
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Xiaowu Xu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Xiaowu Xu
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Xiaowu Xu
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Wensheng Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Wensheng Liu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Wensheng Liu
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Wensheng Liu
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Wenyan Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Wenyan Xu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Wenyan Xu
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Wenyan Xu
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- DOI
- https://doi.org/10.3389/fonc.2022.822039
- Journal volume & issue
-
Vol. 12
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.
Keywords
